The Dawn of Allosteric BCR-ABL1 Drugs: From a Phenotypic Screening Hit to an Approved Drug.
J Med Chem
; 65(11): 7581-7594, 2022 06 09.
Article
en En
| MEDLINE
| ID: mdl-35609336
ABSTRACT
Chronic myeloid leukemia (CML) is driven by the constitutive activity of the BCR-ABL1 fusion oncoprotein. Despite the great success of drugs that target the BCR-ABL1 ATP-binding site in transforming CML into a manageable disease, emerging resistance point mutations impair inhibitor binding, thereby limiting the effectiveness of these drugs. Recently, allosteric inhibitors that interact with the ABL1 myristate-binding site have been shown to awaken an endogenous regulatory mechanism and reset full-length BCR-ABL1 into an inactive assembled state. The discovery and development of these allosteric inhibitors demonstrates an in-depth understanding of the fundamental regulatory mechanisms of kinases. In this review, we illustrate the structural basis of c-ABL1's dynamic regulation of autoinhibition and activation, discuss the discovery of allosteric inhibitors and the characterization of their mechanism of action, present the therapeutic potential of dual binding to delay the development of mutation-driven acquired resistance, and suggest key lessons learned from this program.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Leucemia Mielógena Crónica BCR-ABL Positiva
/
Proteínas de Fusión bcr-abl
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos