In vitro
The lead "switch-control" inhibitor, DCC-2036, can potently inhibit autophosphorylation of ABL and ABL(T315I) enzymes with IC50 of 0.8 nM and 4 nM. DCC-2036 inhibitS Ba/F3 cells expressing BCR-ABL and BCR-ABL(T315I) with IC50 of 19 nM and 63 nM. Ex vivo exposure of CML cells from patients harboring BCR-ABL or BCR-ABL(T315I) to DCC-2036 reveals marked inhibition of colony formation and reduces phosphorylation of the direct BCR-ABL target CrkL. 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.
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