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Bioorg Med Chem Lett. 2016 Jan 15;26(2):534-539. doi: 10.1016/j.bmcl.2015.11.078. Epub 2015 Nov 22.

4-Aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of mutant epidermal growth factor receptor tyrosine kinase.

Author information

1
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
2
Pharmaron Beijing CO. Ltd, No. 6 Taihe Road BDA, Beijing 100176, China.

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.

KEYWORDS:

Dihydrofuropyrimidine; EGFR inhibitor; Epidermal growth factor receptor; Non-covalent

PMID:
26639762
DOI:
10.1016/j.bmcl.2015.11.078
[Indexed for MEDLINE]

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