Discovery of small molecule inhibitors of MAP3K7 (TAK1) that induce apoptosis of distinct subtypes of B-cell lymphoma cells

1292 Despite recent advances with novel therapeutics, there is a high level of unmet need in B-cell malignancies. As part of our on-going target selection efforts we have identified mitogen-activated protein kinase kinase kinase 7 (MAP3K7, TAK1) as a promising novel target for therapeutic intervention in non-Hodgkin’s lymphoma. This kinase mediates the signal transduction induced by environmental stresses and is involved in the control of a variety of cell functions including transcription regulation and apoptosis. While natural product derived molecules were previously reported as MAP3K7 inhibitors no report of small molecules resulting from rational design or medicinal chemistry programs has been published.
 We report the discovery of thiophenecarboxamides MAP3K7 small molecule inhibitors. These compounds inhibit the kinase activity of MAP3K7 in vitro with low nanomolar potency. Optimization of this series guided by structure-based-design will be discussed. Evidence is presented that supports a mechanism of action consistent with inhibition of the MAP3K7 pathway. This is the first time the structure-activity relationship of MAP3K7 inhibition is presented. Furthermore, the cellular activity of these compounds were assessed in a panel of Haem/Onc cell lines and were found to selectively and potently inhibit survival of distinct subtypes of B-cell lymphoma cells. In addition, MAP3K7 inhibitor is found to induce apoptosis in DoHH2 cell lines. These compounds present drug-like properties that make them suitable for preclinical studies.
 In conclusion, small molecule inhibitors of MAP3K7 are reported along with evidence to support that MAP3K7 inhibition induces apoptosis in B-cell lymphoma cells. This chemical series shows promise to generate agents for treatment of B-cell malignancies.