Fig. 5: A schematic diagram of the effects of fadraciclib at 4 h. | Cell Death Discovery

Fig. 5: A schematic diagram of the effects of fadraciclib at 4 h.

From: Interrogation of novel CDK2/9 inhibitor fadraciclib (CYC065) as a potential therapeutic approach for AML

Fig. 5: A schematic diagram of the effects of fadraciclib at 4 h.

A Fadraciclib downregulates E2F1, resulting in cell cycle arrest at G1 phase. Downregulation of RNAPII is the most plausible explanation for the global gene suppression observed. A rapid decrease in short half-life MCL-1 level perturbs a balance in the BCL-2 family. A decrease in the Erk1/2 activity observed in all cell lines tested potentially promotes a reduction in MCL-1 stability and half-life. p38 MAPK is markedly increased in MOLM-13 cell line only, implying that the stress response and apoptosis are highly induced. B Fadraciclib downregulates MCL-1, which activates the intrinsic apoptosis pathway, followed by cell death. Indeed, a rapid decrease in MCL-1 level perturbs a balance in the BCL-2 family, which leads directly to activator BH3-only proteins-binding BAK and BAX, resulting in their homo-oligomerisation and MOMP. Following this, pro-apoptotic proteins within the mitochondrial intermembrane space, for example, Cyt c, DIABLO and HTRA2 are released. Cyt c binds to APAF-1 to form the apoptosome. Once formed, the apoptosome can then recruit and activate the inactive pro-caspase-9. Following this, caspases-3, 6, and 7 are activated and multiple proteolytic events occur. FAD, Fadraciclib; Cip/Kip, cyclin-dependent kinase interacting protein/kinase inhibitory protein; INK4, inhibitors of cyclin-dependent kinase 4; G1, Gap 1 phase; S, Synthesis phase; G2, Gap 2 phase; M, Mitotic phase; BCL-2, B-cell lymphoma 2; BCL-xL, B-cell lymphoma-extra large; BCL-w, B-cell lymphoma 2-like protein 2; BAD, B-cell lymphoma 2-associated death promoter; NOXA, phorbol-12-myristate-13-acetate-induced protein 1; BIM, B-cell lymphoma 2-like protein 11; BID, BH3 interacting-domain death agonist; PUMA, p53 upregulated modulator of apoptosis; BAK, B-cell lymphoma 2 homologous antagonist/killer; BAX, B-cell lymphoma 2-associated X protein; MOMP, mitochondrial outer membrane permeabilisation; Cyt c, cytochrome c; DIABLO, direct inhibitor of apoptosis proteins-binding protein with low pI; HTRA2, high-temperature requirement A serine peptidase 2; APAF-1, apoptotic protease activating factor-1; BIRC5, baculoviral inhibitor of apoptosis repeat-containing 5; XIAP, X-linked inhibitor of apoptosis protein.

Back to article page