Recent progress on third generation covalent EGFR inhibitors

Bioorg Med Chem Lett. 2016 Apr 15;26(8):1861-8. doi: 10.1016/j.bmcl.2016.02.067.

Hengmiao Cheng ¹, Sajiv K Nair ², Brion W Murray ³

Affiliations

1 Oncology Medicinal Chemistry, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States. Electronic address: henry.cheng@pfizer.com.
2 Oncology Medicinal Chemistry, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States.
3 Oncology Research Unit, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States.

PMID: 26968253 DOI: 10.1016/j.bmcl.2016.02.067

Abstract

First generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib and erlotinib) demonstrate excellent clinical efficacy for NSCLC patients carrying EGFR oncogenic mutations (L858R, del exon 19 deletions between Amino acids 746 and 750). Invariable, drug resistance occurs with around 60% of it driven by the EGFR-T790M gatekeeper mutation. To counter the T790M-dependent resistance, third generation covalent EGFR inhibitors have been developed with high potency toward T790M containing mutants and selectivity over WT EGFR. This review provides an overview of the third generation drugs currently in clinical trials and also encompasses novel methodologies developed to discover third generation covalent EGFR drugs.

Keywords

Covalent inhibitor; Drug resistance; EGFR; Lung cancer; NSCLC; Oncogenic mutation; SBDD; T790M.

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