2. Academic Validation
  3. Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor

Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor

  • J Med Chem. 2016 Oct 13;59(19):9080-9093. doi: 10.1021/acs.jmedchem.6b00995.
Bryan K Chan,  Emily J Hanan,  Krista K Bowman,  Marian C Bryan,  Daniel Burdick,  Emily Chan,  Yuan Chen,  Saundra Clausen,  Trisha Dela Vega,  Jennafer Dotson,  Charles Eigenbrot,  Richard L Elliott 1,  Robert A Heald 1,  Philip S Jackson 1,  Jamie D Knight 1,  Hank La,  Michael D Lainchbury 1,  Shiva Malek,  Hans E Purkey,  Gabriele Schaefer,  Stephen Schmidt,  Eileen M Seward 1,  Steve Sideris,  Lily Shao,  Shumei Wang,  Siew Kuen Yeap 1,  Ivana Yen,  Christine Yu,  Timothy P Heffron
Affiliations

Affiliation

  • 1 Charles River Laboratories, 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
PMID: 27564586 DOI: 10.1021/acs.jmedchem.6b00995
Abstract

Inhibitors targeting the activating mutants of the epidermal growth factor receptor (EGFR) have found success in the treatment of EGFR mutant positive non-small-cell lung Cancer. A secondary point mutation (T790M) in the inhibitor binding site has been linked to the acquired resistance against those first generation therapeutics. Herein, we describe the lead optimization of a series of reversible, pan-mutant (L858R, del746-750, T790M/L858R, and T790M/del746-750) EGFR inhibitors. By use of a noncovalent double mutant (T790M/L858R and T790M/del746-750) selective EGFR inhibitor (2) as a starting point, activities against the single mutants (L858R and del746-750) were introduced through a series of structure-guided modifications. The in vitro ADME-PK properties of the lead molecules were further optimized through a number of rational structural changes. The resulting inhibitor (21) exhibited excellent cellular activity against both the single and double mutants of EGFR, demonstrating target engagement in vivo and ADME-PK properties that are suitable for further evaluation. The reversible, noncovalent inhibitors described complement the covalent pan-mutant EGFR inhibitors that have shown encouraging results in recent clinical trials.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100520
    EGFR Inhibitor