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The T315I point mutation situated at the ATP-binding site of BCR/Abl tyrosine kinase remains to be an unmet medical need in treating CML patients. Up to date, none of the approved CML drugs including Imatinib and Dasatinib are able to inhibit this most prevalent BCR/Abl mutation. We have proven that it is a viable approach to address the T315I mutation by small molecule-based rational drug design. Briefly, TG100598, a representative of a benzotriazine class, was previously shown to inhibit Abl and Abl.T315I at high potency in both enzyme and cell proliferation assays. These benzotriazine compounds were evolved into a new class of structurally simplified BCR/Abl inhibitors with enhanced pharmaceutical properties. A representative of this new class, TG101114, has been demonstrated as a more superior BCR/Abl inhibitor than TG100598. Not only did TG101114 inhibit Abl or Abl.T315I enzyme and proliferation of cells expressing either BCR/Abl or BCR/Abl.T315I at submicromolar IC50 or EC50 values, but is has also displayed more desirable PK properties (e.g. oral bioavailability: 20% and T1/2: >5 h) and in vivo efficacy. The growth of BCR/Abl cell-induced tumors in a SCID mouse xenograft model was suppressed by TG101114 at 10 and 30 mg/kg (PO/QD). Consistently, BCR/Abl.T315I-induced STAT5 phosphorylation in the spleens of mice implanted with BCR/Abl.T315I cells was inhibited by TG101114. The ex vivo colony formation assay has unequivocally demonstrated that TG10114 specifically inhibited the BCR/Abl.T315I+ cells isolated from CML patients. The class of TG101114 has been further evolved into a new class of BCR/Abl inhibitors containing the Dasatinib thiazole core (e.g. TG101477) that have shown equal potency in inhibiting BCR/Abl and BCR/Abl.T315I in both enzyme and cell proliferation assays and appealing PK properties. More importantly, compared with Dasatinib, TG101477 has significantly improved kinase selectivity: only 6 of 76 kinases were inhibited by >80% at 500 nM of TG101477. Similar to TG101114, TG101477 specifically inhibited BCR/Abl.T315I+ cells isolated form CML patients in an ex vivo colony formation assay. Therefore, the above two novel classes of BCR/Abl inhibitors represent a great potential to treat the drug resistant CML patients.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA