Mechanism of Kinase Inhibitors

There are 555 kinases in the human body, and perhaps others that have not been identified.  Together they make up the “kinome”.  Some are considered eukaryotic protein kinases and some are atypical.  Eukaryotic kinases can be classified into 8 major groups.  The most important one for cancer treatment is the tyrosine group, and most kinase inhibitor drugs have a tyrosine substrate. Other groups are CK1 (casein kinases); AGC (protein kinase A, G and C); CaMK (calcium/calmodulin-dependent kinases); CMGC (cyclin-dependent kinases, MAP kinases, glycogen synthase kinases, CDC-like kinases); STE (homologues of sterile 7); TKL (tyrosine kinase like); and the RGC (receptor guanylate cyclase) groups.

Much of the molecularly targeted therapy that the medical world has been pursuing in recent decades involves kinase inhibitors.

This website classifies MAbs separately from kinase inhibitors, but some MAbs work by inhibiting kinases.  The drugs Callaix identifies as kinase inhibitors are more precisely called small-molecule kinase inhibitors (SMKIs).  Kinase inhibitors drugs are used in the clinic for more than just cancer.  Arthritis, and other inflammatory and auto-immune diseases, are conditions that doctors treat with these agents, and scientists are trying to find SMKIs that effectively treat lupus, Chron’s Disease, ulcerative colitis, and psoriasis, but oncology is the main branch of medicine that employs kinase inhibitors.  The United States FDA has approved 71 SMKIs (not just for cancer), and another 16 SMKIs have been approved by other agencies around the world.

Type I vs Type II

Medicinal chemists can classify kinase inhibitors by how they work at the molecular level, but this classification has changed over the years.  Initially there were Type I, Type II, and Type III.   Type I inhibitors “bind to the active conformation of a kinase in the ATP pocket,”  At a molecular structure level these drugs often include a heterocyclic ring system that mimics the adenine ring structure of ATP.  Type II is “a small molecule that binds to an inactive (usually Asp-Phe-Gly (DFG)-OUT) confirmation of a kinase,” and the type III inhibitor as “a non-ATP competitive inhibitor” or allosteric inhibitor.  Type II inhibitors tend to be more selective than type I inhibitors.   They bind to the hydrophobic site adjacent to the ATP binding pocket.  Allosteric inhibitors are even more selective; they bind to the kinase outside the ATP-binding pocket.   Later biochemists added type I½ (or 1.5) inhibitors.  An article in Molecular Cancer classified kinase inhibitors into type I, type II, allosteric (type III), substrate directed (type IV) and covalent inhibitors (Type V).  No type IV inhibitors are in clinical use for cancer treatment at this time.

Covalent inhibitors form covalent chemical bonds with amino acid residues on the kinase molecule, thereby inhibiting its mechanism.  Afatinib and Ibrutinib were the first covalent inhibitors approved in 2013; Osimertinib, Acalabrutinib, Dacomitinib, Zanubrutinib , and Neratinib are also covalent inhibitors.

The MEK inhibitors Trametinib, Cobimetanib, and Binimetinib are classified as allosteric inhibitors (Type III).

Type I inhibitors:

Abemaciclib
Acalabrutinib
Alectinib
Avapritinib
Axitinib
Bosutinib
Brigatinib
Cabozantinib
Capmatinib
Ceritinib
Crizotinib
Dabrafenib
Dacomitinib
Dasatinib
Duvelisib
Encorafenib
Erlotinib
Gefitinib
Gilteritinib
Ibrutinib
Idelalisib
Larotrectinib
Lorlatinib
Midostaurin
Neratinib
Osimertinib
Palbociclib
Pazopanib
Ponatinib
Ribociclib
Ruxolitinib
Sunitinib
Tucatinib
Umbralisib
Vandetanib
Vemurafenib

Type II inhibitors:

Entrectinib
Imatinib
Nilotinib
Regorafenib
Ripretinib
Sorafenib
Tivozanib

Type I½ inhibitors:

Alpelisib
Copanlisib
Erdafitinib
Infigratinib
Lapatinib
Lenvatinib

PDF: Type I and Type II Inhibitors

PDF: Type 3 and Type 5 kinase inhibitors

Growth Factor inhibitors

HER2 inhibitor drugs include pertuzumab, rastuzumab, neratinib, lapatinib, ado-trastuzumab emtansine, and dacomitinib.  EGFR inhibitors include gefitinib, neratinib, panitumumab, erlotinib, lapatinib, cetuximab, osimertinib, vandetanib, necitumumab, and dacomitinib.

VEGF/VEGFR inhibitors include pazopanib, sorafenib, ponatinib, bevacizumab, ziv-aflibercept, sunitinib, cabozantinib, axitinib, regorafenib, cabozantinib, vandetanib, ramucirumab, lenvatinib, and bevacizumab.

Sources of information: https://www.nature.com/articles/s41573-021-00252-y, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817855/, https://arxiv.org/ftp/arxiv/papers/1811/1811.09718.pdf