Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study

  • J Med Chem. 2015 Nov 25;58(22):8877-95. doi: 10.1021/acs.jmedchem.5b01412.
Robert Heald  1 ,  Krista K Bowman ,  Marian C Bryan ,  Daniel Burdick ,  Bryan Chan ,  Emily Chan ,  Yuan Chen ,  Saundra Clausen ,  Belen Dominguez-Fernandez  1 ,  Charles Eigenbrot ,  Richard Elliott  1 ,  Emily J Hanan ,  Philip Jackson  1 ,  Jamie Knight  1 ,  Hank La ,  Michael Lainchbury  1 ,  Shiva Malek ,  Sam Mann  1 ,  Mark Merchant ,  Kyle Mortara ,  Hans Purkey ,  Gabriele Schaefer ,  Stephen Schmidt ,  Eileen Seward  1 ,  Steve Sideris ,  Lily Shao ,  Shumei Wang ,  Kuen Yeap  1 ,  Ivana Yen ,  Christine Yu ,  Timothy P Heffron
Affiliations
  • 1. Argenta, Early Discovery Charles River , 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
PMID: 26455919 DOI: 10.1021/acs.jmedchem.5b01412
Abstract

Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell Lung Cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.