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
  • 1. Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: [email protected].
  • 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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