title: Utilization of Structure-Based Design to Identify Novel, Irreversible Inhibitors of EGFR Harboring the T790M Mutation.
abstract: A novel series of covalent inhibitors of EGFR (epidermal growth factor receptor) kinase was discovered through a combination of subset screening and structure-based design. These compounds preferentially inhibit mutant forms of EGFR (activating mutant and T790M mutant) over wild-type EGFR in cellular assays measuring EGFR autophosphorylation and proliferation, suggesting an improved therapeutic index in non-small cell lung cancer patients would be achievable relative to established EGFR inhibitors. We describe our design approaches, resulting in the identification of the lead compound 5, and our efforts to develop an understanding of the structure-activity relationships within this series. In addition, strategies to overcome challenges around metabolic stability and aqueous solubility are discussed. Despite limitations in its physical properties, 5 is orally bioavailable in mice and demonstrates pronounced antitumor activity in in vivo models of mutant EGFR-driven cancers.
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hennessy
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Claudio
authors.initials: C
authors.lastname: Chuaqui
authors.affiliation: Oncology iMed & Discovery Sciences, Innovative Medicines & Early Development, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Ashton
authors.affiliation: Oncology iMed & Discovery Sciences, Innovative Medicines & Early Development, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Colclough
authors.affiliation: Oncology iMed & Discovery Sciences, Innovative Medicines & Early Development, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Darren A E
authors.initials: DA
authors.lastname: Cross
authors.affiliation: Oncology iMed & Discovery Sciences, Innovative Medicines & Early Development, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Judit É
authors.initials: JÉ
authors.lastname: Debreczeni
authors.affiliation: Oncology iMed & Discovery Sciences, Innovative Medicines & Early Development, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Cath
authors.initials: C
authors.lastname: Eberlein
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Lakshmaiah
authors.initials: L
authors.lastname: Gingipalli
authors.affiliation: Oncology iMed & Discovery Sciences, Innovative Medicines & Early Development, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Teresa C M
authors.initials: TC
authors.lastname: Klinowska
authors.affiliation: Oncology iMed & Discovery Sciences, Innovative Medicines & Early Development, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Orme
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Sha
authors.affiliation: Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Wu
keywords: Non-small cell lung cancer; T790M mutation; aminopyrazines; covalent kinase inhibitors; epidermal growth factor receptor; structure-based drug design