SNX-631

Selective inhibitors of Bcr-Abl (prototype – imatinib mesylate, IM, Gleevec®) cause a therapeutic effect in the treatment of the primary process...Senexin B (SenB) and SNX631 were used for selective inhibition of CDK8/19, to suppress Bcr-Abl – IM, dasatinib, nilotinib, PF-114.Results and DiscussionsIt was found that CDK8/19 inhibition by SenB alone does not have an antiproliferative effect on CML cells...These changes were not demonstrated in KU812, where neither SenB sensitization, nor changes in expression of CKIs and c-Myc level were detected.ConclusionInhibition of CDK8/19 helps to overcome the delay of the cell cycle caused by the Bcr-Abl antagonist in CML cells and increase the death of tumor cells. The absence of general toxicity of CDK8/19 inhibitors during prolonged treatment under experimental conditions allows us to recommend CDK8/19 inhibition with targeted therapy of Bcr-Abl-positive tumors in prospect.

Selective CDK8/19 inhibitors (senexin B and SNX631) showed synergistic interactions with lapatinib and trastuzumab in a panel of HER2 BrCa cell lines, overcoming and preventing resistance to HER2-targeting drugs. These effects were associated with decreased tumor cell proliferation and altered recruitment of stromal components to the xenograft tumors. These results suggest potential clinical benefit of combining HER2- and CDK8/19-targeting drugs in the treatment of metastatic HER2 BrCa.