Advances in protein kinase drug discovery through targeting gatekeeper mutations

ABSTRACT

Introduction

Acquired resistance caused by gatekeeper mutations has become a major challenge for approved kinase inhibitors used in the clinic. Consequently, the development of new-generation inhibitors or degraders to overcome clinical resistance has become an important research focus for the field.

Areas covered

This review summarizes the common gatekeeper mutations in druggable kinases and the constantly evolving inhibitors or degraders designed to overcome single or double mutations of gatekeeper residues. Furthermore, the authors provide their perspectives on the medicinal chemistry strategies for addressing clinical resistance with gatekeeper mutations.

Expert opinion

The authors suggest optimizing kinase inhibitors to interact effectively with gatekeeper residues, altering the binding mode or binding pocket to avoid steric clashes, improving binding affinity with the target, utilizing protein degraders, and developing combination therapy. These approaches have the potential to be effective in overcoming resistance due to gatekeeper residues.

KEYWORDS:

• Druggable kinase
• gatekeeper mutation
• acquired resistance
• kinase inhibitors
• drug design

Article highlights

• Gatekeeper residue mutations are frequently observed clinically relevant mutations in targetable kinases.

• Gatekeeper mutations can disrupt critical contacts with inhibitors by altering the size of the side chain, increasing ATP’s affinity for the kinase, or facilitating its ability to enter the active state.

• Gatekeeper mutations can confer resistance to existing kinase inhibitors in various kinases, including but not limited to ALK, TRK, KIT, BTK, RET, ABL, EGFR, FGFR.

• Various strategies have proven effective in addressing the issue of kinase gatekeeper mutations, such as macrocyclic structure, covalent inhibitors, allosteric inhibitors, and degraders, as well as combination therapy.

• Existing kinase inhibitors that can overcome gatekeeper resistance are also faced with challenges, such as combination mutations involving gatekeeper/solvent front, gatekeeper/xDFG, gatekeeper/activation-loop, and other similar mutations.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors appreciate the financial support from the National Natural Science Foundation of China (82204182 and 82273763), the Basic and Applied Basic Research Foundation of Guangdong Province (2022B1515130008, 2023A1515010114), the Open Project of State Key Laboratory of Respiratory Disease (SKLRD-OP-202313) and through the Wang Kuancheng Young Scholarship Program of Jinan University.