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Research Projects

Molecular and functional characterization of small molecule inhibitors to evaluate anti-tumor activity in acute myeloid leukemia

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The survival of acute myeloid leukemia (AML) blasts is dependent on the mitochondrial apoptotic pathway involving BCL-2 family of proteins. Most of the agents, regardless of their categorization as ‘cytotoxic’ or ‘targeted’ ultimately function by activating the mitochondrial apoptotic pathway. In AML, BCL-2 inhibitor (ABT-199) has shown encouraging anti leukemic activity but resistance is emerging due to high expression of MCL-1. In collaboration with Aurigene discovery technologies we have developed a CDK7 inhibitor (AU-14227) which reduces MCL-1 expression in AML cells without affecting the transcriptional profile of normal cells. The purpose of the present study is to determine whether a selective and targeted BCL-2 inhibitor (ABT-199) would cooperate with highly specific CDK7 inhibition via THZ1 or novel AU-14227 to kill AML cells, and to elucidate the molecular mechanisms underlying this phenomenon using in vitro and ex vivo models of AML.

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