title: 4-Aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of mutant epidermal growth factor receptor tyrosine kinase.
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.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Hanan
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Matt
authors.initials: M
authors.lastname: Baumgardner
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Marian C
authors.initials: MC
authors.lastname: Bryan
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Fan
authors.affiliation: Pharmaron Beijing CO. Ltd, No. 6 Taihe Road BDA, Beijing 100176, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Gu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schaefer
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Ivana
authors.initials: I
authors.lastname: Yen
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Yu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffron
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004285:Dogs; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D022781:Hepatocytes / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D006860:Hydrogen Bonding; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D007211:Indoles
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005663:Furans; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000596361:osimertinib; D007211:Indoles
keywords: Dihydrofuropyrimidine; EGFR inhibitor; Epidermal growth factor receptor; Non-covalent