BCR-ABL, a transforming tyrosine kinase active in >90% of CML cases, and it has been possible to inhibit of BCR-ABL kinase in leukemic cells without adversely affecting the normal cell population. However, a significant proportion of patients treated chronically with imatinib (Gleevec) develop drug resistance because of the acquisition of mutations in kinase domain of BCR-ABL. While new compounds like dasatinib and nilotinib are active against most of these mutant enzymes, one mutation, the T315I, has been refractory to most new inhibitors. Here, we describe new small molecule inhibitors of both wild type and T315I mutant BCR-ABL kinases. These compounds belong to indolinone family, which has not previously been used in bcr-abl inhibition, and inhibit BCR-ABL and T315I mutation variant in a non-ATP competitive fashion. These compounds are water soluble with suitable pharmacokinetic profile and are. These compounds exhibit potent activity against K562 cells and Baf3 cells carrying mutant bcr-abl genes. One of these compounds, ON 88210 showed inhibition of BCR-ABL (WT and T315I forms) auto-phosphorylation and STAT-5 phosphorylation in cultured cells. The mechanism of action of ON 88210 seems to be different from imatinib (Gleevec) as this compound does not affect the phosphorylation of CRK-L. Further development and differentiation of these compounds from imatinib will be described.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3718.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009