Drug intelligence / Profile preview

imatinib + dasatinib + nilotinib + bosutinib + ponatinib + asciminib

Development stage
Unknown
Lead developer
Novartis
Modality
Small Molecules
Administration
Oral
01

Overview

This is a theoretical multi-drug combination consisting of six BCR-ABL–targeted tyrosine kinase inhibitors (TKIs): imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and asciminib. Imatinib, dasatinib, nilotinib, bosutinib, and ponatinib are ATP-competitive small-molecule TKIs that inhibit the BCR-ABL1 fusion tyrosine kinase driving Philadelphia chromosome–positive leukemias, with overlapping but distinct kinase selectivity profiles and differential activity against a spectrum of BCR-ABL1 resistance mutations.[2][11][15][19] Asciminib is a novel small-molecule “STAMP” inhibitor that binds the ABL myristoyl pocket, allosterically inhibiting BCR-ABL1 and retaining activity against many kinase-domain mutants including T315I.[16][20] All six agents are approved individually (not as a fixed combination) primarily for chronic-phase chronic myeloid leukemia (CML), with some also indicated in accelerated or blast phase and in Ph+ acute lymphoblastic leukemia.[2][9][17][20] Although various dual combinations such as asciminib with imatinib, nilotinib, dasatinib, or ponatinib have been explored in preclinical and early clinical settings to overcome resistance or compound mutations, there is no approved or clinically established regimen that combines all six drugs simultaneously.[1][4][8][12][22][25]

02

Targets

ABL1 myristoyl pocketFLT3 (Fms related receptor tyrosine kinase 3)KIT (c-KIT proto-oncogene receptor tyrosine kinase)PDGFRA (Platelet-derived growth factor receptor alpha)SFK (SRC family kinases)

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