2. Academic Validation
  3. Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study

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

Affiliation

  • 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.

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