title: Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study.
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.
authors.affiliation: Argenta, Early Discovery Charles River , 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Heald
authors.forename: Krista K
authors.initials: KK
authors.lastname: Bowman
authors.forename: Marian C
authors.initials: MC
authors.lastname: Bryan
authors.forename: Daniel
authors.initials: D
authors.lastname: Burdick
authors.forename: Bryan
authors.initials: B
authors.lastname: Chan
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Saundra
authors.initials: S
authors.lastname: Clausen
authors.affiliation: Argenta, Early Discovery Charles River , 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Belen
authors.initials: B
authors.lastname: Dominguez-Fernandez
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.affiliation: Argenta, Early Discovery Charles River , 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Elliott
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Hanan
authors.affiliation: Argenta, Early Discovery Charles River , 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Jackson
authors.affiliation: Argenta, Early Discovery Charles River , 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Jamie
authors.initials: J
authors.lastname: Knight
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.affiliation: Argenta, Early Discovery Charles River , 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Lainchbury
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.affiliation: Argenta, Early Discovery Charles River , 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Sam
authors.initials: S
authors.lastname: Mann
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Kyle
authors.initials: K
authors.lastname: Mortara
authors.forename: Hans
authors.initials: H
authors.lastname: Purkey
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schaefer
authors.forename: Stephen
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Argenta, Early Discovery Charles River , 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Eileen
authors.initials: E
authors.lastname: Seward
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.forename: Lily
authors.initials: L
authors.lastname: Shao
authors.forename: Shumei
authors.initials: S
authors.lastname: Wang
authors.affiliation: Argenta, Early Discovery Charles River , 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Kuen
authors.initials: K
authors.lastname: Yeap
authors.forename: Ivana
authors.initials: I
authors.lastname: Yen
authors.forename: Christine
authors.initials: C
authors.lastname: Yu
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffron
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D004285:Dogs; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D055785:Gene Knockdown Techniques; D018773:Genes, erbB-1 / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008055:Lipids / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008055:Lipids; D066246:ErbB Receptors