Discovery of a potent inhibitor of MELK that inhibits expression of the anti-apoptotic protein Mcl-1 and TNBC cell growth

作者：Edupuganti Ramakrishna; Taliaferro Juliana M; Wang Qiantao; Xie Xuemei; Cho Eun Jeong; Vidhu Fnu; Ren Pengyu; Anslyn Eric V; Bartholomeusz Chandra; Dalby Kevin N^*

来源：Bioorganic & Medicinal Chemistry, 2017, 25(9): 2609-2616.

DOI：10.1016/j.bmc.2017.03.018

• Maternal embryonic leucine zipper kinase (MELK)
• MELK inhibitor
• Indolinone derivatives
• Triple negative breast cancer (TNBC)
• Screening hits
• Kinase inhibitor

Despite recent advances in molecularly directed therapy, triple negative breast cancer (TNBC) remains one of the most aggressive forms of breast cancer, still without a suitable target for specific inhibitors. Maternal embryonic leucine zipper kinase (MELK) is highly expressed in TNBC, where level of overexpression correlates with poor prognosis and an aggressive disease course. Herein, we describe the discovery through targeted kinase inhibitor library screening, and structure-guided design of a series of ATP-competitive indolinone derivatives with subnanomolar inhibition constants towards MELK. The most potent compound, 17, inhibits the expression of the anti-apoptotic protein Mcl-1 and proliferation of TNBC cells exhibiting selectivity for cells expressing high levels of MELK. These studies suggest that further elaboration of 17 will furnish MELK-selective inhibitors with potential for development in preclinical models of TNBC and other cancers.

• 出版日期2017-5-1