학술논문

Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036.
Document Type
article
Source
Cancer cell. 19(4)
Subject
Animals
Cell Line
Tumor
Cell Proliferation: drug effects
Cell Survival: drug effects
Drug Design
Fusion Proteins
bcr-abl: antagonists & inhibitors
chemistry
Humans
Leukemia
Myelogenous
Chronic
BCR-ABL Positive: drug therapy
Male
Mice
Mice
Inbred BALB C
Mutation
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma: drug therapy
Protein Conformation
Protein Kinase Inhibitors: pharmacology
Protein-Tyrosine Kinases: antagonists & inhibitors
chemistry
Language
Abstract
Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead "switch-control" inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph(+) leukemia.