title: Discovery of a potent inhibitor of MELK that inhibits expression of the anti-apoptotic protein Mcl-1 and TNBC cell growth.
abstract: 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.
authors.affiliation: Division of Chemical Biology & Medicinal Chemistry, The University of Texas at Austin, TX 78712, USA; The Targeted Drug Discovery and Development Program, College of Pharmacy, The University of Texas at Austin, TX 78712, USA; Department of Chemistry, The University of Texas at Austin, TX 78712, USA.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Edupuganti
authors.affiliation: Division of Chemical Biology & Medicinal Chemistry, The University of Texas at Austin, TX 78712, USA.
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Taliaferro
authors.affiliation: Division of Chemical Biology & Medicinal Chemistry, The University of Texas at Austin, TX 78712, USA.
authors.forename: Qiantao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Xie
authors.affiliation: The Targeted Drug Discovery and Development Program, College of Pharmacy, The University of Texas at Austin, TX 78712, USA.
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Cho
authors.affiliation: Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Fnu
authors.initials: F
authors.lastname: Vidhu
authors.affiliation: Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, TX 78712, USA.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Ren
authors.affiliation: Department of Chemistry, The University of Texas at Austin, TX 78712, USA.
authors.forename: Eric V
authors.initials: EV
authors.lastname: Anslyn
authors.affiliation: Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chandra
authors.initials: C
authors.lastname: Bartholomeusz
authors.affiliation: Division of Chemical Biology & Medicinal Chemistry, The University of Texas at Austin, TX 78712, USA; The Targeted Drug Discovery and Development Program, College of Pharmacy, The University of Texas at Austin, TX 78712, USA. Electronic address: dalby@austin.utexas.edu.
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Dalby
mesh_terms: D000083:Acetanilides / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000083:Acetanilides; D000970:Antineoplastic Agents; D007211:Indoles; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; C000625356:methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxoindoline-5-carboxylate; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases; C530716:nintedanib
keywords: Indolinone derivatives; Kinase inhibitor; MELK inhibitor; Maternal embryonic leucine zipper kinase (MELK); Screening hits; Triple negative breast cancer (TNBC)