4-Aminoindazolyl-dihydrofuro[3, 4-d]pyrimidines as non-covalent inhibitors of mutant epidermal growth factor receptor tyrosine kinase. Issue 2 (15th January 2016)

• Record Type: Journal Article
• Authors: Hanan, Emily J.; Baumgardner, Matt; Bryan, Marian C.; Chen, Yuan; Eigenbrot, Charles; Fan, Peter; Gu, Xiao-Hui; La, Hank; Malek, Shiva; Purkey, Hans E.; Schaefer, Gabriele; Schmidt, Stephen; Sideris, Steve; Yen, Ivana; Yu, Christine; Heffron, Timothy P.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 2(2016)
• Page Start: 534
• Page End: 539
• Publication Date: 2016-01-15
• Subjects: Dihydrofuropyrimidine -- Epidermal growth factor receptor -- EGFR inhibitor -- Non-covalent; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.11.078
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The treatment of epidermal growth factor receptor (EGFR)-driven non-small cell lung cancers with the T790M resistance mutation remains a significant unmet medical need. We report the identification of 4-aminoindazolyl-dihydrofuro[3, 4- d ]pyrimidines as non-covalent inhibitors of EGFR, with excellent activity against the T790M resistance double mutants and initial single activating mutants. Using an optimization strategy focused on structure-based design and improving PK properties through metabolite identification, we obtained advanced leads with high oral exposure.