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

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 9; pp. 2609 - 2616
• Main Authors: Edupuganti, Ramakrishna, Taliaferro, Juliana M., Wang, Qiantao, Xie, Xuemei, Cho, Eun Jeong, Vidhu, Fnu, Ren, Pengyu, Anslyn, Eric V., Bartholomeusz, Chandra, Dalby, Kevin N.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.05.2017; Elsevier
• Subjects: Acetanilides - chemical synthesis; Acetanilides - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biochemistry & Molecular Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Humans; Indoles - chemical synthesis; Indoles - pharmacology; Indolinone derivatives; Kinase inhibitor; Life Sciences & Biomedicine; Maternal embryonic leucine zipper kinase (MELK); MELK inhibitor; Molecular Docking Simulation; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Pharmacology & Pharmacy; Physical Sciences; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Science & Technology; Screening hits; Triple negative breast cancer (TNBC); MELK inhibitor; Screening hits; Triple negative breast cancer (TNBC); Indolinone derivatives; Kinase inhibitor; Maternal embryonic leucine zipper kinase (MELK); DESIGN; PROLIFERATION; NEGATIVE BREAST-CANCER; BRAIN-TUMORS; INDOLINONES; POOR-PROGNOSIS; THERAPEUTIC TARGET; GLIOMA STEM-CELLS; SERINE/THREONINE KINASE; LEUCINE-ZIPPER KINASE
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2017.03.018

[Display omitted] 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.