2. Academic Validation
  3. From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors

From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors

  • Bioorg Med Chem Lett. 2017 Jul 1;27(13):2974-2981. doi: 10.1016/j.bmcl.2017.05.016.
Jun Liang 1,  Sharada Labadie 2,  Birong Zhang 2,  Daniel F Ortwine 2,  Snahel Patel 2,  Maia Vinogradova 2,  James R Kiefer 2,  Till Mauer 2,  Victor S Gehling 3,  Jean-Christophe Harmange 3,  Richard Cummings 3,  Tommy Lai 4,  Jiangpeng Liao 4,  Xiaoping Zheng 4,  Yichin Liu 2,  Amy Gustafson 2,  Erica Van der Porten 2,  Weifeng Mao 4,  Bianca M Liederer 2,  Gauri Deshmukh 2,  Le An 2,  Yingqing Ran 2,  Marie Classon 2,  Patrick Trojer 3,  Peter S Dragovich 2,  Lesley Murray 2
Affiliations

Affiliations

  • 1 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: liang.jun@gene.com.
  • 2 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 3 Constellation Pharmaceuticals Inc., 215 First Street, Suite 200, Cambridge, MA 02142, USA.
  • 4 WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
PMID: 28512031 DOI: 10.1016/j.bmcl.2017.05.016
Abstract

A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5mg/kg resulted in unbound Cmax ∼2-fold of its cell potency (PC9 H3K4Me3 0.96μM), meeting our criteria for an in vivo tool compound from a new scaffold.

Keywords

Epigenetics; KDM5; KDM5 inhibitors; Overcome cancer resistance; Structure-based drug discovery.

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