Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight

Smith, Troy and Sprague, Elizabeth and Wang, Kate and Mathieu, Simon and Chen, Zhuoliang and Mishina, Yuji and Feng, Yun and Shakya, Subarna and Chen, Dongshu and Meyer, Matthew and Brazell, Tres and Straub, Christopher and Sage, David and Wright, Kirk and Chen, Xin and Duca, Jose and Kim, Sean and Tian, Li and Martin, Eric and Hurov, Kristen and Shao, Wenlin and Yan-Neale, Yan (2016) Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight. Journal of Medicinal Chemistry, 59 (10). pp. 4711-4723. ISSN 1520-4804

Abstract

MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.

Item Type: Article
Date Deposited: 29 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/27656

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.