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Drugging p53 in cancer: one protein, many targets

Nature Reviews Drug Discovery volume 22, pages 127–144 (2023)Cite this article

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Abstract

Mutations in the TP53 tumour suppressor gene are very frequent in cancer, and attempts to restore the functionality of p53 in tumours as a therapeutic strategy began decades ago. However, very few of these drug development programmes have reached late-stage clinical trials, and no p53-based therapeutics have been approved in the USA or Europe so far. This is probably because, as a nuclear transcription factor, p53 does not possess typical drug target features and has therefore long been considered undruggable. Nevertheless, several promising approaches towards p53-based therapy have emerged in recent years, including improved versions of earlier strategies and novel approaches to make undruggable targets druggable. Small molecules that can either protect p53 from its negative regulators or restore the functionality of mutant p53 proteins are gaining interest, and drugs tailored to specific types of p53 mutants are emerging. In parallel, there is renewed interest in gene therapy strategies and p53-based immunotherapy approaches. However, major concerns still remain to be addressed. This Review re-evaluates the efforts made towards targeting p53-dysfunctional cancers, and discusses the challenges encountered during clinical development.

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Fig. 1: Tumour-suppressive effects of wild-type p53 and oncogenic effects of mutant p53.
Fig. 2: Numbers of p53-targeted clinical trials by year and treatment category.
Fig. 3: p53-based small molecules for cancer therapy.
Fig. 4: New antibody-based strategies to target p53 in cancer cells.
Fig. 5: p53 can influence immunotherapy by modulating the tumour immune microenvironment.
Fig. 6: p53-based genetic therapies.

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References

  1. Barbosa, A. et al. Gene panel tumor testing in ovarian cancer patients significantly increases the yield of clinically actionable germline variants beyond BRCA1/BRCA2. Cancers 12, 2834 (2020).

    Article  CAS  Google Scholar 

  2. Hoe, K. K., Verma, C. S. & Lane, D. P. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat. Rev. Drug Discov. 13, 217–236 (2014).

    Article  Google Scholar 

  3. Sabapathy, K. & Lane, D. P. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat. Rev. Clin. Oncol. 15, 13–30 (2018).

    Article  CAS  Google Scholar 

  4. Bykov, V. J. N., Eriksson, S. E., Bianchi, J. & Wiman, K. G. Targeting mutant p53 for efficient cancer therapy. Nat. Rev. Cancer 182, 89–102 (2017).

    Google Scholar 

  5. Cheok, C. F. & Lane, D. P. Exploiting the p53 pathway for therapy. Cold Spring Harb. Perspect. Med. 7, a026310 (2017).

    Article  Google Scholar 

  6. Levine, A. J. p53: 800 million years of evolution and 40 years of discovery. Nat. Rev. Cancer 20, 471–480 (2020).

    Article  CAS  Google Scholar 

  7. Kastan, M. B., Canman, C. E. & Leonard, C. J. p53, cell cycle control and apoptosis: implications for cancer. Cancer Metastasis Rev. 14, 3–15 (1995).

    Article  CAS  Google Scholar 

  8. Williams, A. B. & Schumacher, B. p53 in the DNA-damage-repair process. Cold Spring Harb. Perspect. Med. 6, a026070 (2016).

    Article  Google Scholar 

  9. Fridman, J. S. & Lowe, S. W. Control of apoptosis by p53. Oncogene 22, 9030–9040 (2003).

    Article  CAS  Google Scholar 

  10. Kastenhuber, E. R. & Lowe, S. W. Putting p53 in context. Cell 170, 1062–1078 (2017).

    Article  CAS  Google Scholar 

  11. Speidel, D. Transcription-independent p53 apoptosis: an alternative route to death. Trends Cell Biol. 20, 14–24 (2010).

    Article  CAS  Google Scholar 

  12. Vaseva, A. V. & Moll, U. M. The mitochondrial p53 pathway. Biochim. Biophys. Acta 1787, 414 (2009).

    Article  CAS  Google Scholar 

  13. Giorgi, C. et al. p53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent manner. Proc. Natl Acad. Sci. USA 112, 1779–1784 (2015).

    Article  CAS  Google Scholar 

  14. Maiuri, M. C. et al. Autophagy regulation by p53. Curr. Opin. Cell Biol. 22, 181–185 (2010).

    Article  CAS  Google Scholar 

  15. Tan, X. et al. p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi. Sci. Adv. 7, eabf4885 (2021).

    Article  CAS  Google Scholar 

  16. Mantovani, F., Collavin, L. & Del Sal, G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ. 26, 199–212 (2018).

    Article  Google Scholar 

  17. Sicari, D. et al. Mutant p53 improves cancer cells’ resistance to endoplasmic reticulum stress by sustaining activation of the UPR regulator ATF6. Oncogene 38, 6184–6195 (2019).

    Article  CAS  Google Scholar 

  18. Walerych, D. et al. Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer. Nat. Cell Biol. 18, 897–909 (2016).

    Article  CAS  Google Scholar 

  19. Capaci, V. et al. Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome. Nat. Commun. 11, 3945 (2020).

    Article  CAS  Google Scholar 

  20. Weisz, L., Oren, M. & Rotter, V. Transcription regulation by mutant p53. Oncogene 26, 2202–2211 (2007).

    Article  CAS  Google Scholar 

  21. Kim, M. P. & Lozano, G. Mutant p53 partners in crime. Cell Death Differ. 25, 161–168 (2018).

    Article  CAS  Google Scholar 

  22. Amit, M. et al. Loss of p53 drives neuron reprogramming in head and neck cancer. Nature 578, 449–454 (2020).

    Article  CAS  Google Scholar 

  23. Blagih, J., Buck, M. D. & Vousden, K. H. p53, cancer and the immune response. J. Cell Sci. 133, jcs237453 (2020).

    Article  CAS  Google Scholar 

  24. Wellenstein, M. D. et al. Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis. Nature 572, 538–542 (2019). This paper shows that p53 loss in cancer cells promotes a tumour-supportive immune microenvironment in multiple mouse models of breast cancer.

    Article  CAS  Google Scholar 

  25. Cooks, T. et al. Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nat. Commun. 9, 771 (2018).

    Article  Google Scholar 

  26. Pilley, S., Rodriguez, T. A. & Vousden, K. H. Mutant p53 in cell-cell interactions. Genes Dev. 35, 433–448 (2021).

    Article  CAS  Google Scholar 

  27. Olivier, M., Hollstein, M. & Hainaut, P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb. Perspect. Biol. 2, a001008 (2010).

    Article  Google Scholar 

  28. Shchors, K. et al. Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy. Proc. Natl Acad. Sci. USA 110, E1480–E1489 (2013).

    Article  CAS  Google Scholar 

  29. Martins, C. P., Brown-Swigart, L. & Evan, G. I. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127, 1323–1334 (2006).

    Article  CAS  Google Scholar 

  30. Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007).

    Article  CAS  Google Scholar 

  31. Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007).

    Article  CAS  Google Scholar 

  32. Sánchez-Rivera, F. J. et al. Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration. Proc. Natl Acad. Sci. USA 118, e2019740118 (2021).

    Article  Google Scholar 

  33. Foster, B. A., Coffey, H. A., Morin, M. J. & Rastinejad, F. Pharmacological rescue of mutant p53 conformation and function. Science 286, 2507–2510 (1999).

    Article  CAS  Google Scholar 

  34. Wang, W., Takimoto, R., Rastinejad, F. & El-Deiry, W. S. Stabilization of p53 by CP-31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 20 or MDM2 binding. Mol. Cell. Biol. 23, 2171–2181 (2003).

    Article  CAS  Google Scholar 

  35. Rippin, T. M. et al. Characterization of the p53-rescue drug CP-31398 in vitro and in living cells. Oncogene 21, 2119–2129 (2002).

    Article  CAS  Google Scholar 

  36. Bykov, V. J. N. et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat. Med. 8, 282–288 (2002). This is the first report of PRIMA-1, a small molecule that restores wtp53-like functionality to multiple p53 mutants and induces apoptosis in cancer cells.

    Article  CAS  Google Scholar 

  37. Lambert, J. M. R. et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 15, 376–388 (2009).

    Article  CAS  Google Scholar 

  38. Bykov, V. J. N. et al. Targeting of mutant p53 and the cellular redox balance by APR-246 as a strategy for efficient cancer therapy. Front. Oncol. 6, 21 (2016).

    Article  Google Scholar 

  39. Chipuk, J. E., Maurer, U., Green, D. R. & Schuler, M. Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription. Cancer Cell 4, 371–381 (2003).

    Article  CAS  Google Scholar 

  40. Saha, M. N., Chen, Y., Chen, M. H., Chen, G. & Chang, H. Small molecule MIRA-1 induces in vitro and in vivo anti-myeloma activity and synergizes with current anti-myeloma agents. Br. J. Cancer 110, 2224–2231 (2014).

    Article  CAS  Google Scholar 

  41. Zache, N. et al. Mutant p53 targeting by the low molecular weight compound STIMA-1. Mol. Oncol. 2, 70–80 (2008).

    Article  Google Scholar 

  42. Bou-Hanna, C. et al. Acute cytotoxicity of MIRA-1/NSC19630, a mutant p53-reactivating small molecule, against human normal and cancer cells via a caspase-9-dependent apoptosis. Cancer Lett. 359, 211–217 (2015).

    Article  CAS  Google Scholar 

  43. Tal, P. et al. Cancer therapeutic approach based on conformational stabilization of mutant p53 protein by small peptides. Oncotarget 7, 11817–11837 (2016).

    Article  Google Scholar 

  44. Ali, D. et al. APR-246 exhibits anti-leukemic activity and synergism with conventional chemotherapeutic drugs in acute myeloid leukemia cells. Eur. J. Haematol. 86, 206–215 (2011).

    Article  CAS  Google Scholar 

  45. Zandi, R. et al. PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53. Clin. Cancer Res. 17, 2830–2841 (2011).

    Article  CAS  Google Scholar 

  46. Liu, X. et al. Small molecule induced reactivation of mutant p53 in cancer cells. Nucleic Acids Res. 41, 6034–6044 (2013).

    Article  CAS  Google Scholar 

  47. Bykov, V. J. N. et al. PRIMA-1MET synergizes with cisplatin to induce tumor cell apoptosis. Oncogene 24, 3484–3491 (2005).

    Article  CAS  Google Scholar 

  48. Mohell, N. et al. APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells. Cell Death Dis. 6, e1794 (2015).

    Article  CAS  Google Scholar 

  49. Fransson, Å. et al. Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant high-grade serous ovarian cancer. J. Ovarian Res. 9, 27 (2016).

    Article  Google Scholar 

  50. Sallman, D. A. et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J. Clin. Oncol. 39, 1584–1594 (2021).

    Article  CAS  Google Scholar 

  51. Cluzeau, T. et al. Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase II study by the Groupe Francophone des Myélodysplasies (GFM). J. Clin. Oncol. 39, 1575–1583 (2021).

    Article  CAS  Google Scholar 

  52. Aprea https://ir.aprea.com/news-releases/news-release-details/aprea-therapeutics-announces-positive-results-phase-2-trial (2021).

  53. Kravchenko, J. E. et al. Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway. Proc. Natl Acad. Sci. USA 105, 6302–6307 (2008).

    Article  CAS  Google Scholar 

  54. Zhang, S. et al. Small-molecule NSC59984 restores p53 pathway signaling and antitumor effects against colorectal cancer via p73 activation and degradation of mutant p53. Cancer Res. 75, 3842–3852 (2015).

    Article  CAS  Google Scholar 

  55. Xu, J. et al. Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. Nat. Chem. Biol. 7, 285–295 (2011).

    Article  CAS  Google Scholar 

  56. Zhang, S., Zhou, L. & El-Deiry, W. S. Small-molecule NSC59984 induces mutant p53 degradation through a ROS–ERK2–MDM2 axis in cancer cells. Mol. Cancer Res. 20, 622–636 (2022).

    Article  CAS  Google Scholar 

  57. Wang, G. & Fersht, A. R. Propagation of aggregated p53: cross-reaction and coaggregation vs. seeding. Proc. Natl Acad. Sci. USA 112, 2443 (2015).

    Article  CAS  Google Scholar 

  58. Soragni, A. et al. A designed inhibitor of p53 aggregation rescues p53 tumor suppression in ovarian carcinomas. Cancer Cell 29, 90–103 (2016).

    Article  CAS  Google Scholar 

  59. Palanikumar, L. et al. Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function. Nat. Commun. 12, 3962 (2021).

    Article  CAS  Google Scholar 

  60. Joerger, A. C., Ang, H. C. & Fersht, A. R. Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Proc. Natl Acad. Sci. USA 103, 15056–15061 (2006).

    Article  CAS  Google Scholar 

  61. Boeckler, F. M. et al. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc. Natl Acad. Sci. USA 105, 10360–10365 (2008).

    Article  CAS  Google Scholar 

  62. ASCO. https://meetings.asco.org/abstracts-presentations/207594 (2022).

  63. Yu, X., Vazquez, A., Levine, A. J. & Carpizo, D. R. Allele-specific p53 mutant reactivation. Cancer Cell 21, 614–625 (2012).

    Article  CAS  Google Scholar 

  64. Yu, X. et al. Thiosemicarbazones functioning as zinc metallochaperones to reactivate mutant p53. Mol. Pharmacol. 91, 567–575 (2017).

    Article  CAS  Google Scholar 

  65. Salim, K. Y., Maleki Vareki, S., Danter, W. R. & Koropatnick, J. COTI-2, a novel small molecule that is active against multiple human cancer cell lines in vitro and in vivo. Oncotarget 7, 41363–41379 (2016).

    Article  Google Scholar 

  66. Lindemann, A. et al. COTI-2, a novel thiosemicarbazone derivative, exhibits antitumor activity in HNSCC through p53-dependent and -independent mechanisms. Clin. Cancer Res. 25, 5650–5662 (2019).

    Article  CAS  Google Scholar 

  67. Westin, S. N. et al. Abstract CT033: Safety and early efficacy signals for COTI-2, an orally available small molecule targeting p53, in a phase I trial of recurrent gynecologic cancer. Cancer Res. 78, CT033 (2018).

    Article  Google Scholar 

  68. Chen, S. et al. Arsenic trioxide rescues structural p53 mutations through a cryptic allosteric site. Cancer Cell 39, 225–239.e8 (2021). This paper reports that ATO, used for treating acute promyelocytic leukaemia, can reactivate structural p53 mutants and induce p53-dependent tumour suppression.

    Article  Google Scholar 

  69. Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. L. & Vogelstein, B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 358, 80–83 (1992).

    Article  CAS  Google Scholar 

  70. Oliner, J. D., Saiki, A. Y. & Caenepeel, S. The role of MDM2 amplification and overexpression in tumorigenesis. Cold Spring Harb. Perspect. Med. 6, a026336 (2016).

    Article  Google Scholar 

  71. Vassilev, L. T. et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844–848 (2004).

    Article  CAS  Google Scholar 

  72. Vu, B. et al. Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development. ACS Med. Chem. Lett. 4, 466–469 (2013).

    Article  CAS  Google Scholar 

  73. Ray-Coquard, I. et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 13, 1133–1140 (2012).

    Article  CAS  Google Scholar 

  74. Andreeff, M. et al. Results of the phase 1 trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin. Cancer Res. 22, 868 (2016).

    Article  CAS  Google Scholar 

  75. Kim, E. S. & Shohet, J. M. Reactivation of p53 via MDM2 inhibition. Cell Death Dis. 6, e1936 (2015).

    Article  CAS  Google Scholar 

  76. Iancu-Rubin, C. et al. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Exp. Hematol. 42, 137–145.e5 (2014).

    Article  CAS  Google Scholar 

  77. Xue, Y. et al. Bortezomib stabilizes and activates p53 in proliferative compartments of both normal and tumor tissues in vivo. Cancer Res. 79, 3595–3607 (2019).

    Article  CAS  Google Scholar 

  78. Yee, K. et al. Murine double minute 2 inhibition alone or with cytarabine in acute myeloid leukemia: results from an idasanutlin phase 1/1b study. Leuk. Res. 100, 106489 (2021).

    Article  CAS  Google Scholar 

  79. Montesinos, P. et al. MIRROS: a randomized, placebo-controlled, phase III trial of cytarabine ± idasanutlin in relapsed or refractory acute myeloid leukemia. Future Oncol. 16, 807–815 (2020).

    Article  CAS  Google Scholar 

  80. Konopleva, M. Y. et al. Idasanutlin plus cytarabine in relapsed or refractory acute myeloid leukemia: results of the MIRROS trial. Blood Adv. 6, 4147–4156 (2022).

    CAS  Google Scholar 

  81. Mascarenhas, J. et al. Oral idasanutlin in patients with polycythemia vera. Blood 134, 525–533 (2019).

    Article  CAS  Google Scholar 

  82. Mascarenhas, J. et al. Safety and efficacy of idasanutlin in patients (pts) with hydroxyurea (HU)-resistant/intolerant polycythemia vera (PV): results of an international phase II study. Blood 136, 29–31 (2020).

    Article  Google Scholar 

  83. Fang, D. D. et al. MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia models. Cell Death Disco. 7, 90 (2021).

    Article  CAS  Google Scholar 

  84. Yi, H. et al. A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma. J. Exp. Clin. Cancer Res. 37, 97 (2018).

    Article  Google Scholar 

  85. Sun, D. et al. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J. Med. Chem. 57, 1454–1472 (2014).

    Article  CAS  Google Scholar 

  86. Canon, J. et al. The MDM2 inhibitor AMG 232 demonstrates robust antitumor efficacy and potentiates the activity of p53-inducing cytotoxic agents. Mol. Cancer Ther. 14, 649–658 (2015).

    Article  CAS  Google Scholar 

  87. Verstovsek, S. et al. BOREAS: a global phase 3 study of KRT-232, a first-in-class murine double minute 2 (MDM2) inhibitor in TP53WT relapsed/refractory (R/R) myelofibrosis (MF). J. Clin. Oncol. 39 (suppl.15), TPS7057 (2021).

    Article  Google Scholar 

  88. Erba, H. P. et al. Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia. Blood Adv. 3, 1939–1949 (2019).

    Article  CAS  Google Scholar 

  89. Jeay, S. et al. Dose and schedule determine distinct molecular mechanisms underlying the efficacy of the p53-MDM2 inhibitor HDM201. Cancer Res. 78, 6257–6267 (2018).

    Article  CAS  Google Scholar 

  90. Gounder, M. M. et al. A phase 1 study of the MDM2 inhibitor DS-3032b in patients (pts) with advanced solid tumors and lymphomas. J. Clin. Oncol. 34 (suppl.15), 2581 (2016).

    Article  Google Scholar 

  91. Wade, M., Li, Y. C. & Wahl, G. M. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat. Rev. Cancer 13, 83–96 (2013).

    Article  CAS  Google Scholar 

  92. Carvajal, L. A. et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci. Transl. Med. 10, 3003 (2018).

    Article  Google Scholar 

  93. Tan, Y. S., Lane, D. P. & Verma, C. S. Stapled peptide design: principles and roles of computation. Drug. Discov. Today 21, 1642–1653 (2016).

    Article  CAS  Google Scholar 

  94. Bernal, F. et al. A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell 18, 411–422 (2010).

    Article  CAS  Google Scholar 

  95. Li, Y. C. et al. A versatile platform to analyze low-affinity and transient protein-protein interactions in living cells in real time. Cell Rep. 9, 1946–1958 (2014).

    Article  CAS  Google Scholar 

  96. Chang, Y. S. et al. Stapled α-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc. Natl Acad. Sci. USA 110, E3445–E3454 (2013).

    Article  CAS  Google Scholar 

  97. Pairawan, S. et al. First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models. Breast Cancer Res 23, 29 (2021).

    Article  CAS  Google Scholar 

  98. Meric-Bernstam, F. et al. Phase I trial of a novel stapled peptide ALRN-6924 disrupting MDMX- and MDM2-mediated inhibition of WT p53 in patients with solid tumors and lymphomas. J. Clin. Oncol. 35, 2505 (2017).

    Article  Google Scholar 

  99. Cheng, X. et al. Leveraging the multivalent p53 peptide-MdmX interaction to guide the improvement of small molecule inhibitors. Nat. Commun. 13, 1087 (2022).

    Article  CAS  Google Scholar 

  100. Mares, A. et al. Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2. Commun. Biol. 3, 140 (2020).

    Article  CAS  Google Scholar 

  101. Schneekloth, A. R., Pucheault, M., Tae, H. S. & Crews, C. M. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics. Bioorg. Med. Chem. Lett. 18, 5904–5908 (2008).

    Article  CAS  Google Scholar 

  102. Hines, J., Lartigue, S., Dong, H., Qian, Y. & Crews, C. M. MDM2-recruiting PROTAC offers superior, synergistic antiproliferative activity via simultaneous degradation of BRD4 and stabilization of p53. Cancer Res. 79, 251–262 (2019).

    Article  CAS  Google Scholar 

  103. Li, Y. et al. Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression. J. Med. Chem. 62, 448–466 (2019).

    Article  CAS  Google Scholar 

  104. Wang, B. et al. Development of MDM2 degraders based on ligands derived from Ugi reactions: lessons and discoveries. Eur. J. Med. Chem. 219, 113425 (2021).

    Article  CAS  Google Scholar 

  105. He, S. et al. Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer. Acta Pharm. Sin. B 11, 1617–1628 (2021).

    Article  CAS  Google Scholar 

  106. Issaeva, N. et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat. Med. 10, 1321–1328 (2004).

    Article  CAS  Google Scholar 

  107. Zhao, C. Y., Szekely, L., Bao, W. & Selivanova, G. Rescue of p53 function by small-molecule RITA in cervical carcinoma by blocking E6-mediated degradation. Cancer Res. 70, 3372–3381 (2010).

    Article  CAS  Google Scholar 

  108. Weilbacher, A., Gutekunst, M., Oren, M., Aulitzky, W. E. & Van Der Kuip, H. RITA can induce cell death in p53-defective cells independently of p53 function via activation of JNK/SAPK and p38. Cell Death Dis. 5, e1318 (2014).

    Article  CAS  Google Scholar 

  109. Wiegering, A. et al. Reactivating p53 and inducing tumor apoptosis (RITA) enhances the response of RITA-sensitive colorectal cancer cells to chemotherapeutic agents 5-fluorouracil and oxaliplatin. Neoplasia 19, 301–309 (2017).

    Article  CAS  Google Scholar 

  110. Yang, J. et al. Small-molecule activation of p53 blocks hypoxia-inducible factor 1alpha and vascular endothelial growth factor expression in vivo and leads to tumor cell apoptosis in normoxia and hypoxia. Mol. Cell. Biol. 29, 2243–2253 (2009).

    Article  CAS  Google Scholar 

  111. Celegato, M. et al. A novel small-molecule inhibitor of the human papillomavirus E6–p53 interaction that reactivates p53 function and blocks cancer cells growth. Cancer Lett. 470, 115–125 (2020).

    Article  CAS  Google Scholar 

  112. Zhang, J. et al. A small-molecule inhibitor of MDMX suppresses cervical cancer cells via the inhibition of E6–E6AP–p53 axis. Pharmacol. Res. 177, 106128 (2022).

    Article  CAS  Google Scholar 

  113. Donehower, L. A. et al. Integrated analysis of TP53 gene and pathway alterations in the cancer genome atlas. Cell Rep. 28, 1370–1384.e5 (2019).

    Article  CAS  Google Scholar 

  114. Bidou, L., Bugaud, O., Belakhov, V., Baasov, T. & Namy, O. Characterization of new-generation aminoglycoside promoting premature termination codon readthrough in cancer cells. RNA Biol. 14, 378–388 (2017).

    Article  Google Scholar 

  115. Floquet, C., Deforges, J., Rousset, J. P. & Bidou, L. Rescue of non-sense mutated p53 tumor suppressor gene by aminoglycosides. Nucleic Acids Res. 39, 3350–3362 (2011).

    Article  CAS  Google Scholar 

  116. Martin, L. et al. Identification and characterization of small molecules that inhibit nonsense-mediated rna decay and suppress nonsense p53 mutations. Cancer Res. 74, 3104–3113 (2014).

    Article  CAS  Google Scholar 

  117. Dabrowski, M., Bukowy-Bieryllo, Z. & Zietkiewicz, E. Advances in therapeutic use of a drug-stimulated translational readthrough of premature termination codons. Mol. Med. 24, 25 (2018).

    Article  Google Scholar 

  118. Alexandrova, E. M. et al. Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. Nature 523, 352–356 (2015).

    Article  CAS  Google Scholar 

  119. Padmanabhan, A. et al. USP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells. Nat. Commun. 9, 1270 (2018).

    Article  Google Scholar 

  120. Hassin, O. et al. Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients. Nat. Commun. 13, 2800 (2022).

    Article  CAS  Google Scholar 

  121. Mukherjee, S. et al. Cross-talk between mutant p53 and p62/SQSTM1 augments cancer cell migration by promoting the degradation of cell adhesion proteins. Proc. Natl Acad. Sci. USA 119, e2119644119 (2022).

    Article  CAS  Google Scholar 

  122. Kennedy, M. C. & Lowe, S. W. Mutant p53: it’s not all one and the same. Cell Death Differ. 29, 983–987 (2022).

    Article  CAS  Google Scholar 

  123. Alvarado-Ortiz, E. et al. Mutant p53 gain-of-function: role in cancer development, progression, and therapeutic approaches. Front. Cell Dev. Biol. 8, 607670 (2021).

    Article  Google Scholar 

  124. Lauwen, M. M. et al. Self-tolerance does not restrict the CD4+ T-helper response against the p53 tumor antigen. Cancer Res. 68, 893–900 (2008).

    Article  CAS  Google Scholar 

  125. Chikamatsu, K. et al. Generation of anti-p53 cytotoxic T lymphocytes from human peripheral blood using autologous dendritic cells. Clin. Cancer Res. 5, 1281–1288 (1999).

    CAS  Google Scholar 

  126. Röpke, M. et al. Spontaneous human squamous cell carcinomas are killed by a human cytotoxic T lymphocyte clone recognizing a wild-type p53-derived peptide. Proc. Natl Acad. Sci. USA 93, 14704–14707 (1996).

    Article  Google Scholar 

  127. Vierboom, M. P. M. et al. Tumor eradication by wild-type p53-specific cytotoxic T lymphocytes. J. Exp. Med. 186, 695–704 (1997).

    Article  CAS  Google Scholar 

  128. Speetjens, F. M. et al. Induction of p53-specific immunity by a p53 synthetic long peptide vaccine in patients treated for metastatic colorectal cancer. Clin. Cancer Res. 15, 1086–1095 (2009).

    Article  CAS  Google Scholar 

  129. Vermeij, R. et al. Potentiation of a p53-SLP vaccine by cyclophosphamide in ovarian cancer: a single-arm phase II study. Int. J. Cancer 131, E670–E680 (2012).

    Article  CAS  Google Scholar 

  130. Leffers, N. et al. Long-term clinical and immunological effects of p53-SLP® vaccine in patients with ovarian cancer. Int. J. Cancer 130, 105–112 (2012).

    Article  CAS  Google Scholar 

  131. Hardwick, N. R. et al. p53MVA therapy in patients with refractory gastrointestinal malignancies elevates p53-specific CD8+ T-cell responses. Clin. Cancer Res. 20, 4459–4470 (2014).

    Article  CAS  Google Scholar 

  132. Hardwick, N. R. et al. p53-Reactive T cells are associated with clinical benefit in patients with platinum-resistant epithelial ovarian cancer after treatment with a p53 vaccine and gemcitabine chemotherapy. Clin. Cancer Res. 24, 1315–1325 (2018).

    Article  CAS  Google Scholar 

  133. Barfoed, A. M. et al. Cytotoxic T-lymphocyte clones, established by stimulation with the HLA-A2 binding p5365-73 wild type peptide loaded on dendritic cells In vitro, specifically recognize and lyse HLA-A2 tumour cells overexpressing the p53 protein. Scand. J. Immunol. 51, 128–133 (2000).

    Article  CAS  Google Scholar 

  134. Antonia, S. J. et al. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin. Cancer Res. 12, 878–887 (2006).

    Article  CAS  Google Scholar 

  135. Chiappori, A. A., Soliman, H., Janssen, W. E., Antonia, S. J. & Gabrilovich, D. I. INGN-225: a dendritic cell-based p53 vaccine (Ad.p53-DC) in small cell lung cancer: observed association between immune response and enhanced chemotherapy effect. Expert. Opin. Biol. Ther. 10, 983–991 (2010).

    Article  CAS  Google Scholar 

  136. Chiappori, A. A. et al. Randomized-controlled phase II trial of salvage chemotherapy after immunization with a TP53-transfected dendritic cell-based vaccine (Ad.p53-DC) in patients with recurrent small cell lung cancer. Cancer Immunol. Immunother. 68, 517–527 (2019).

    Article  CAS  Google Scholar 

  137. Met, Ö., Balslev, E., Flyger, H. & Svane, I. M. High immunogenic potential of p53 mRNA-transfected dendritic cells in patients with primary breast cancer. Breast Cancer Res. Treat. 125, 395–406 (2010).

    Article  Google Scholar 

  138. Li, D. et al. Development of a T-cell receptor mimic antibody against wild-type p53 for cancer immunotherapy. Cancer Res. 77, 2699–2711 (2017).

    Article  CAS  Google Scholar 

  139. Low, L., Goh, A., Koh, J., Lim, S. & Wang, C. I. Targeting mutant p53-expressing tumours with a T cell receptor-like antibody specific for a wild-type antigen. Nat. Commun. 10, 5382 (2019).

    Article  Google Scholar 

  140. Cheever, M. A. et al. The prioritization of cancer antigens: a National Cancer Institute pilot project for the acceleration of translational research. Clin. Cancer Res. 15, 5323–5337 (2009).

    Article  Google Scholar 

  141. Balachandran, V. et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, 512–516 (2017).

    Article  CAS  Google Scholar 

  142. Deniger, D. C. et al. T-cell responses to TP53 ‘Hotspot’ mutations and unique neoantigens expressed by human ovarian cancers. Clin. Cancer Res. 24, 5562–5573 (2018).

    Article  CAS  Google Scholar 

  143. Malekzadeh, P. et al. Neoantigen screening identifies broad TP53 mutant immunogenicity in patients with epithelial cancers. J. Clin. Invest. 129, 1109–1114 (2019).

    Article  Google Scholar 

  144. Malekzadeh, P. et al. Antigen experienced T cells from peripheral blood recognize p53 neoantigens. Clin. Cancer Res. 26, 1267–1276 (2020).

    Article  CAS  Google Scholar 

  145. You, G. et al. Bispecific antibodies: a smart arsenal for cancer immunotherapies. Vaccines 9, 724 (2021).

    Article  CAS  Google Scholar 

  146. Hsiue, E. H. C. et al. Targeting a neoantigen derived from a common TP53 mutation. Science 371, eabc8697 (2021). This paper reports a bispecific antibody, highly specific to the p53(R175H) mutation, which activates T cells to kill cancer cells presenting a p53(R175H)-derived neoantigen in vitro and in vivo.

    Article  CAS  Google Scholar 

  147. Levine, A. J. P53 and the immune response: 40 years of exploration-a plan for the future. Int. J. Mol. Sci. 21, 541 (2020).

    Article  CAS  Google Scholar 

  148. Cortez, M. A. et al. PDL1 regulation by p53 via miR-34. J. Natl Cancer Inst. 108, djv303 (2015). This paper reports that wtp53 can downregulate PDL1 in cancer cells, suggesting a mechanism whereby loss of wtp53 can render such cells more refractory to immune attack.

    Google Scholar 

  149. Textor, S. et al. Human NK cells are alerted to induction of p53 in cancer cells by upregulation of the NKG2D ligands ULBP1 and ULBP2. Cancer Res. 71, 5998–6009 (2011).

    Article  CAS  Google Scholar 

  150. Zhou, X. et al. Pharmacological activation of p53 triggers viral mimicry response thereby abolishing tumor immune evasion and promoting anti-tumor immunity. Cancer Discov. 11, 3090–3105 (2021).

    Article  CAS  Google Scholar 

  151. Maddalena, M. et al. TP53 missense mutations in PDAC are associated with enhanced fibrosis and an immunosuppressive microenvironment. Proc. Natl Acad. Sci. USA 118, e2025631118 (2021).

    Article  CAS  Google Scholar 

  152. PMVPharma. PMV Pharmaceuticals Announces a Clinical Trial Collaboration with Merck to Evaluate PC14586 in Combination with KEYTRUDA® (pembrolizumab) in Patients with Advanced Solid Tumors. GlobeNewswire (18 July 2022); go.nature.com/3fyQKDo

  153. Moskovits, N., Kalinkovich, A., Bar, J., Lapidot, T. & Oren, M. p53 Attenuates cancer cell migration and invasion through repression of SDF-1/CXCL12 expression in stromal fibroblasts. Cancer Res. 66, 10671–10676 (2006).

    Article  CAS  Google Scholar 

  154. Fang, D. D. et al. MDM2 inhibitor APG-115 synergizes with PD-1 blockade through enhancing antitumor immunity in the tumor microenvironment. J. Immunother. Cancer 7, 327 (2019). This paper describes the enhanced antitumour effect of combining a p53 activating molecule (APG-115) with an anti-PD1 antibody, attributed to the effect of APG-115 on the tumour immune microenvironment.

    Article  Google Scholar 

  155. Tolcher, A. W. et al. Preliminary results of a phase II study of alrizomadlin (APG-115), a novel, small-molecule MDM2 inhibitor, in combination with pembrolizumab in patients (pts) with unresectable or metastatic melanoma or advanced solid tumors that have failed immuno-oncologic (I-O) drugs. J. Clin. Oncol. 39, 2506 (2021).

    Article  Google Scholar 

  156. Kim, S.-S., Harford, J. B., Moghe, M., Rait, A. & Chang, E. H. Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor. Oncoimmunology 7, e1484982 (2018).

    Article  Google Scholar 

  157. Chada, S. et al. Tumor suppressor immune gene therapy to reverse immunotherapy resistance. Cancer Gene Ther. 29, 825–834 (2022).

    Article  CAS  Google Scholar 

  158. Wang, D. & Wang, K. An overview of development in gene therapeutics in China. Gene Ther. 27, 338–348 (2020).

    Article  CAS  Google Scholar 

  159. Goswami, R. et al. Gene therapy leaves a vicious cycle. Front. Oncol. 9, 297 (2019).

    Article  Google Scholar 

  160. Zhang, W. W. et al. The first approved gene therapy product for cancer ad-p53 (gendicine): 12 years in the clinic. Hum. Gene Ther. 29, 160–179 (2018).

    Article  CAS  Google Scholar 

  161. Xia, Y., Du, Z., Wang, X. & Li, X. Treatment of uterine sarcoma with rAd-p53 (gendicine) followed by chemotherapy: clinical study of TP53 gene therapy. Hum. Gene Ther. 29, 242–250 (2018).

    Article  CAS  Google Scholar 

  162. Li, Y. et al. Selective intra-arterial infusion of rAd-p53 with chemotherapy for advanced oral cancer: a randomized clinical trial. BMC Med. 12, 16 (2014).

    Article  CAS  Google Scholar 

  163. Liu, S. et al. Randomized, controlled phase II study of post-surgery radiotherapy combined with recombinant adenoviral human p53 gene therapy in treatment of oral cancer. Cancer Gene Ther. 20, 375–378 (2013).

    Article  CAS  Google Scholar 

  164. Gabrilovich, D. I. INGN 201 (Advexin): adenoviral p53 gene therapy for cancer. Expert Opin. Biol. Ther. 6, 823–832 (2006).

    Article  CAS  Google Scholar 

  165. Atencio, I. A. et al. Biological activities of a recombinant adenovirus p53 (SCH 58500) administered by hepatic arterial infusion in a phase 1 colorectal cancer trial. Cancer Gene Ther. 13, 169–181 (2006).

    Article  CAS  Google Scholar 

  166. Buller, R. E. et al. A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer. Cancer Gene Ther. 9, 553–566 (2002).

    Article  CAS  Google Scholar 

  167. Zeimet, A. G. & Marth, C. Why did p53 gene therapy fail in ovarian cancer? Lancet Oncol. 4, 415–422 (2003).

    Article  CAS  Google Scholar 

  168. Li, Y. et al. Expert consensus on the clinical application of recombinant adenovirus human p53 for head and neck cancers. Int. J. Oral. Sci. 13, 38 (2021).

    Article  Google Scholar 

  169. Tamura, R. E. et al. Induction of oxidants distinguishes susceptibility of prostate carcinoma cell lines to p53 gene transfer mediated by an improved adenoviral vector. Hum. Gene Ther. 28, 639–653 (2017).

    Article  CAS  Google Scholar 

  170. Chen, S. et al. A surface charge-switchable and folate modified system for co-delivery of proapoptosis peptide and p53 plasmid in cancer therapy. Biomaterials 77, 149–163 (2016).

    Article  CAS  Google Scholar 

  171. Misra, S. K., Naz, S., Kondaiah, P. & Bhattacharya, S. A cationic cholesterol based nanocarrier for the delivery of p53-EGFP-C3 plasmid to cancer cells. Biomaterials 35, 1334–1346 (2014).

    Article  CAS  Google Scholar 

  172. Rejeeth, C. & Kannan, S. p53 Gene therapy of human breast carcinoma: using a transferrin-modified silica nanoparticles. Breast Cancer 23, 101–110 (2016).

    Article  Google Scholar 

  173. Kim, S. S., Rait, A., Kim, E., Pirollo, K. F. & Chang, E. H. A tumor-targeting p53 nanodelivery system limits chemoresistance to temozolomide prolonging survival in a mouse model of glioblastoma multiforme. Nanomedicine 11, 301–311 (2015).

    Article  CAS  Google Scholar 

  174. Senzer, N. et al. Phase I study of a systemically delivered p53 nanoparticle in advanced solid tumors. Mol. Ther. 21, 1096–1103 (2013).

    Article  CAS  Google Scholar 

  175. Pirollo, K. F. et al. Safety and efficacy in advanced solid tumors of a targeted nanocomplex carrying the p53 gene used in combination with docetaxel: a phase 1b study. Mol. Ther. 24, 1697–1706 (2016).

    Article  CAS  Google Scholar 

  176. Kong, N. et al. Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition. Sci. Transl. Med. 11, 1565 (2019). This paper describes the use of synthetic p53 mRNA as a potential anticancer treatment.

    Article  Google Scholar 

  177. Xiao, Y. et al. Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy. Nat. Commun. 13, 758 (2022).

    Article  CAS  Google Scholar 

  178. Sobol, R. E. et al. Meta-analysis of adenoviral p53 gene therapy clinical trials in recurrent head and neck squamous cell carcinoma. medRxiv https://doi.org/10.1101/2021.01.06.20248743 (2021).

    Article  Google Scholar 

  179. Martinez, L. A. et al. Synthetic small inhibiting RNAs: efficient tools to inactivate oncogenic mutations and restore p53 pathways. Proc. Natl Acad. Sci. USA 99, 14849–14854 (2002).

    Article  CAS  Google Scholar 

  180. Ubby, I. et al. Cancer therapeutic targeting using mutant–p53-specific siRNAs. Oncogene 38, 3415–3427 (2019).

    Article  CAS  Google Scholar 

  181. Mirgayazova, R. et al. Therapeutic editing of the TP53 gene: is CRISPR/Cas9 an option? Genes 11, 704 (2020).

    Article  CAS  Google Scholar 

  182. Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016).

    Article  CAS  Google Scholar 

  183. Haapaniemi, E., Botla, S., Persson, J., Schmierer, B. & Taipale, J. CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response. Nat. Med. 24, 927–930 (2018).

    Article  CAS  Google Scholar 

  184. Ihry, R. J. et al. p53 inhibits CRISPR–Cas9 engineering in human pluripotent stem cells. Nat. Med. 24, 939–946 (2018).

    Article  CAS  Google Scholar 

  185. Enache, O. M. et al. Cas9 activates the p53 pathway and selects for p53-inactivating mutations. Nat. Genet. 52, 662–668 (2020).

    Article  CAS  Google Scholar 

  186. Michaelis, M. et al. Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. Cell Death Dis. 2, e243 (2011).

    Article  CAS  Google Scholar 

  187. Chapeau, E. A. et al. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf−/− mouse model. Proc. Natl Acad. Sci. USA 114, 3151–3156 (2017).

    Article  CAS  Google Scholar 

  188. Latif, A. L. et al. BRD4-mediated repression of p53 is a target for combination therapy in AML. Nat. Commun. 12, 241 (2021).

    Article  CAS  Google Scholar 

  189. Pan, R. et al. Synthetic lethality of combined Bcl-2 inhibition and p53 activation in AML: mechanisms and superior antileukemic efficacy. Cancer Cell 32, 748–760.e6 (2017).

    Article  CAS  Google Scholar 

  190. Daver, N. G. et al. Safety, efficacy, pharmacokinetic (PK) and biomarker analyses of BCL2 inhibitor venetoclax (Ven) plus MDM2 inhibitor idasanutlin (idasa) in patients (pts) with relapsed or refractory (R/R) AML: a phase Ib, non-randomized, open-label study. Blood 132, 767–767 (2018).

    Article  Google Scholar 

  191. Fischer, M. Mice are not humans: the case of p53. Trends Cancer 7, 12–14 (2021).

    Article  CAS  Google Scholar 

  192. Horejs, C. Organ chips, organoids and the animal testing conundrum. Nat. Rev. Mater. 6, 372–373 (2021).

    Article  Google Scholar 

  193. Gavert, N. et al. Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer. Nat. Cancer 3, 219–231 (2022).

    Article  CAS  Google Scholar 

  194. Hong, D. S. et al. KRAS G12C inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 383, 1207–1217 (2020).

    Article  CAS  Google Scholar 

  195. Degtjarik, O. et al. Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ). Nat. Commun. 12, 7057 (2021).

    Article  CAS  Google Scholar 

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Acknowledgements

Work in the authors’ lab is supported in part by grants from the Dr Miriam and Sheldon G. Adelson Medical Research Foundation, a Center of Excellence from the Israel Science Foundation, the Israel Science Foundation within the Israel Precision Medicine Partnership programme, the Rising Tide Foundation, Quintrigen, The Robert Bosch Stiftung GmbH and the Berthold Leibinger Stiftung GmbH, the United States–Israel Binational Science Foundation (BSF), Jerusalem, Israel, and the Moross Integrated Cancer Center.

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    Ori Hassin & Moshe Oren

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M.O. consults for Quintrigen.

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Glossary

Michael acceptor

Michael addition is a process of addition of a carbanion or another nucleophile to an α,β-unsaturated carbonyl compound. Michael acceptors are the substituent groups on the activated unsaturated compound. The ability of Michael acceptors to form conjugates with peptides bearing nucleophilic groups provides them with a broad spectrum of potential biological effects.

Stapled peptides

Short peptides locked in a specific conformation by an external brace formed by covalent binding between two amino acid side chains. This allows the molecule to be kept in an α-helical structure with high hydrophobicity, facilitating the crossing of biological membranes.

Bispecific antibodies

Artificial antibodies that possess two binding sites, designed to recognize two different epitopes or antigens. One of the major applications of bispecific antibodies is to bridge two different cell types.

Indels

Insertions or deletions of one or more nucleotides in a DNA sequence.

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Hassin, O., Oren, M. Drugging p53 in cancer: one protein, many targets. Nat Rev Drug Discov 22, 127–144 (2023). https://doi.org/10.1038/s41573-022-00571-8

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