The Philadelphia chromosome translocation creates a BCR-ABL fusion gene that encodes a constitutively active BCR-ABL tyrosine kinase, which gives rise to chronic myelogenous leukemia (CML). The clinical success of imatinib (Gleevec) demonstrated that BCR-ABL tyrosine kinase inhibitors can provide effective treatment for CML. However, some CML patients treated with imatinib develop resistance leading to disease progression. The majority of resistance is due to point mutations in BCR-ABL, which give rise to active mutant enzymes that are insensitive to imatinib. In all, ∼30 imatinib-resistant BCR-ABL mutants have been identified in clinical isolates. The T315I mutant represents ∼20% of clinically observed mutations, making it one of the most common causes of resistance. Second-generation BCR-ABL inhibitors, including AMN-107 and BMS-354825, inhibit many of the clinically relevant mutants but not T315I. Mutant T315I BCR-ABL is, therefore, an important and challenging target for discovery of CML therapeutics. We have applied a proprietary X-ray crystallographic fragment-based lead discovery platform (FAST™) and structure-guided lead optimization to identify potent inhibitors of wild-type BCR-ABL and the four most common mutants, including T315I. Our lead discovery efforts yielded five chemical series that inhibit both wild-type (WT) and T315I BCR-ABL. Compounds in our most advanced lead series potently inhibit proliferation of K562 cells and Ba/F3 cells with WT BCR-ABL and the vast majority of the clinically relevant BCR-ABL mutations, including M244V, G250E, Q252H, Y253F, Y253H, E255K, F311L, T315I, F317L, M351T, F359V, V279I, L387M, H396P, and H396R (see below). Further details describing in vitro and in vivo profiling and efficacy testing of these novel BCR-ABL T315I inhibitors will be presented.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]