Overcoming Secondary Mutations of Type II Kinase Inhibitors.
J Med Chem
; 67(12): 9776-9788, 2024 Jun 27.
Article
in En
| MEDLINE
| ID: mdl-38837951
ABSTRACT
Type II kinase inhibitors bind in the "DFG-out" kinase conformation and are generally considered to be more potent and selective than type I inhibitors, which target a DFG-in conformation. Nine type II inhibitors are currently clinically approved, with more undergoing clinical development. Resistance-conferring secondary mutations emerged with the first series of type II inhibitors, most commonly at residues within the kinase activation loop and at the "gatekeeper" position. Recently, new inhibitors have been developed to overcome such mutations; however, mutations activating other pathways (and/or other targets) have subsequently emerged on occasion. Here, we systematically summarize the secondary mutations that confer resistance to type II inhibitors, the structural basis for resistance, newer inhibitors designed to overcome resistance, as well as the challenges and opportunities for the development of new inhibitors to overcome secondary kinase domain mutations.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Kinase Inhibitors
/
Mutation
Limits:
Animals
/
Humans
Language:
En
Journal:
J Med Chem
/
J. med. chem
/
Journal of medicinal chemistry
Journal subject:
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: