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Beyond PI3Ks: targeting phosphoinositide kinases in disease

Nature Reviews Drug Discovery volume 22, pages 357–386 (2023)Cite this article

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Abstract

Lipid phosphoinositides are master regulators of almost all aspects of a cell’s life and death and are generated by the tightly regulated activity of phosphoinositide kinases. Although extensive efforts have focused on drugging class I phosphoinositide 3-kinases (PI3Ks), recent years have revealed opportunities for targeting almost all phosphoinositide kinases in human diseases, including cancer, immunodeficiencies, viral infection and neurodegenerative disease. This has led to widespread efforts in the clinical development of potent and selective inhibitors of phosphoinositide kinases. This Review summarizes our current understanding of the molecular basis for the involvement of phosphoinositide kinases in disease and assesses the preclinical and clinical development of phosphoinositide kinase inhibitors.

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Fig. 1: Phosphoinositides and the phosphoinositide kinases that generate them.
Fig. 2: Structure–function, inhibition and therapeutic targeting of PIKfyve.
Fig. 3: Structure–function, and inhibition of the PI4P5Ks and PI5P4Ks.
Fig. 4: Structure–function, inhibition and therapeutic targeting of PI4KA and PI4KB.
Fig. 5: Structure–function, inhibition and therapeutic targeting of class II PI3Ks.
Fig. 6: Structure–function, inhibition and therapeutic targeting of class III PI3Ks.

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Acknowledgements

J.E.B. is supported by the Natural Science and Engineering Research Council (Discovery grant NSERC-2020-04241), the Michael Smith Foundation for Health Research (Scholar Award 17686), the Canadian Institute of Health Research (CIHR Project grant 168998) and the Cancer Research Society (operating grant CRS-843232). J.T. is supported by the Swiss National Science Foundation (#310030_207635). B.M.E. receives research funding from NCI (R01 CA237536, CBC under contract no. 75N91019D00024, task order no. 75N91020F00003) and ACS (RSG-20-064-01-TBE, TLC-21-156-01). G.R.V.H. receives funding from NIGMS (R35 GM119412) and NCATS (R03TR003624). The authors are grateful to R. Wills, A. Shaw and C. Weckerly for valuable discussions and suggestions for the manuscript. They apologize to all authors whose work could not be mentioned because of the limitations on the number of references that could be cited.

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Authors and Affiliations

  1. Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada

    John E. Burke

  2. Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, British Columbia, Canada

    John E. Burke

  3. Department of BioMedical Research, University of Bern, Bern, Switzerland

    Joanna Triscott

  4. Sanford Burnham Prebys, La Jolla, CA, USA

    Brooke M. Emerling

  5. Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Gerald R. V. Hammond

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Correspondence to John E. Burke, Brooke M. Emerling or Gerald R. V. Hammond.

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J.E.B. reports personal fees from Scorpion Therapeutics and Olema Oncology; and research grants from Novartis. J.T., B.M.E. and G.R.V.H. declare no competing interests.

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Glossary

Acute myeloid leukaemia

(AML). A fast-growing cancer of the blood and bone marrow.

Alzheimer disease

A progressive brain disorder that affects memory and other cognitive abilities.

Amyotrophic lateral sclerosis

(ALS). A rare neurological disease that affects neurons responsible for controlling voluntary muscle movement.

B cell non-Hodgkin lymphoma

(B-NHL). Cancer that arises when B cells, a type of lymphocyte that normally fights infections by producing antibodies to neutralize foreign invaders, start to grow uncontrollably, eventually overwhelming healthy cells.

Charcot–Marie–Tooth disease

A group of inherited disorders that cause nerve damage. Also referred to as hereditary motor and sensory neuropathy.

Creutzfeldt–Jacob disease

(CJD). A rapidly progressive degenerative brain disorder that leads to dementia and death.

Cryptosporidiosis

A diarrhoeal disease caused by a microscopic parasite called Cryptosporidium, with particular prevalence in children and immunocompromised individuals.

Endocytosis

A cellular process by which cells internalize substances from their external environment.

Frontotemporal dementia

(FTD). An uncommon type of dementia that is a result of damage to neurons in the frontal and temporal lobes of the brain, which causes problems in behaviour and language.

Glioblastoma

(GBM). A fast-growing type of central nervous system tumour that forms from the glial tissue of the brain and spinal cord.

Macroautophagy

A fundamental degradative pathway for cytosolic components, such as proteins, RNA, DNA, lipids and organelles. It involves the sequestering of such cytosolic material in double-membraned structures called autophagosomes, followed by membrane trafficking to the lysosome for degradation and recycling.

Malaria

A disease transmitted by the bite of infected female mosquitoes caused by Plasmodium parasites (five species infect humans, with two species, Plasmodium vivax and Plasmodium falciparum, posing the largest threat).

Parkinson disease

A central nervous system disorder which is associated with a deficiency of the neurotransmitter dopamine and affects movement often resulting in tremors.

Primary lateral sclerosis

(PLS). A rare neuromuscular disease that affects the central motor neurons and is characterized by the gradual weakness and stiffness of muscles.

p53 null tumours

Tumours that are deficient in either the tumour suppressor TP53 gene or the functional p53 protein product, which induces apoptosis, cell cycle arrest or senescence in response to distinct stimuli.

TTC7A deficiency

A rare genetic disorder caused by dysfunction of a gene (TTC7A), which causes diarrhoea, inflammation of the intestines, bowel obstructions, immune dysfunction and an inability to absorb nutrients.

Viral pathogens

Viruses that can infect and replicate within human cells and cause disease.

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Burke, J.E., Triscott, J., Emerling, B.M. et al. Beyond PI3Ks: targeting phosphoinositide kinases in disease. Nat Rev Drug Discov 22, 357–386 (2023). https://doi.org/10.1038/s41573-022-00582-5

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