Discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers |
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Authors: | William Kemnitzer Nilantha Sirisoma Chris May Ben Tseng John Drewe Sui Xiong Cai |
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Institution: | EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA |
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Abstract: | We report the discovery of N-((benzod]1,3]dioxol-5-yl)methyl)-6-phenylthieno3,2-d]pyrimidin-4-amine (2a) as an apoptosis inducer using our proprietary cell- and caspase-based ASAP HTS assay, and SAR study of HTS hit 2a which led to the discovery of 4-anilino-N-methylthieno3,2-d]pyrimidines and 4-anilino-N-methylthieno2,3-d]pyrimidines as potent apoptosis inducers. Compounds 5d and 5e were the most potent with EC50 values of 0.008 and 0.004 μM in T47D human breast cancer cells, respectively. Compound 5d was found to be highly active in the MX-1 breast cancer model. Functionally, compounds 5d and 5e both induced apoptosis through inhibition of tubulin polymerization. |
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