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

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

  • Bioorg Med Chem. 2017 May 1;25(9):2609-2616. doi: 10.1016/j.bmc.2017.03.018.
Ramakrishna Edupuganti 1,  Juliana M Taliaferro 2,  Qiantao Wang 2,  Xuemei Xie 3,  Eun Jeong Cho 4,  Fnu Vidhu 3,  Pengyu Ren 5,  Eric V Anslyn 6,  Chandra Bartholomeusz 3,  Kevin N Dalby 7
Affiliations

Affiliations

  • 1 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.
  • 2 Division of Chemical Biology & Medicinal Chemistry, The University of Texas at Austin, TX 78712, USA.
  • 3 Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 4 The Targeted Drug Discovery and Development Program, College of Pharmacy, The University of Texas at Austin, TX 78712, USA.
  • 5 Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, TX 78712, USA.
  • 6 Department of Chemistry, The University of Texas at Austin, TX 78712, USA.
  • 7 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.
PMID: 28351607 DOI: 10.1016/j.bmc.2017.03.018
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.

Keywords

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

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101515
    98.67%, MELK Inhibitor