title: Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor.
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.
authors: Bryan K
authors: BK
authors: Chan
authors: Emily J
authors: EJ
authors: Hanan
authors: Krista K
authors: KK
authors: Bowman
authors: Marian C
authors: MC
authors: Bryan
authors: Daniel
authors: D
authors: Burdick
authors: Emily
authors: E
authors: Chan
authors: Yuan
authors: Y
authors: Chen
authors: Saundra
authors: S
authors: Clausen
authors: Trisha
authors: T
authors: Dela Vega
authors: Jennafer
authors: J
authors: Dotson
authors: Charles
authors: C
authors: Eigenbrot
authors: Charles River Laboratories, 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors: Richard L
authors: RL
authors: Elliott
authors: Charles River Laboratories, 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors: Robert A
authors: RA
authors: Heald
authors: Charles River Laboratories, 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors: Philip S
authors: PS
authors: Jackson
authors: Charles River Laboratories, 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors: Jamie D
authors: JD
authors: Knight
authors: Hank
authors: H
authors: La
authors: Charles River Laboratories, 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors: Michael D
authors: MD
authors: Lainchbury
authors: Shiva
authors: S
authors: Malek
authors: Hans E
authors: HE
authors: Purkey
authors: Gabriele
authors: G
authors: Schaefer
authors: Stephen
authors: S
authors: Schmidt
authors: Charles River Laboratories, 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors: Eileen M
authors: EM
authors: Seward
authors: Steve
authors: S
authors: Sideris
authors: Lily
authors: L
authors: Shao
authors: Shumei
authors: S
authors: Wang
authors: Charles River Laboratories, 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors: Siew Kuen
authors: SK
authors: Yeap
authors: Ivana
authors: I
authors: Yen
authors: Christine
authors: C
authors: Yu
authors: Timothy P
authors: TP
authors: Heffron
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors