PDBsum entry 5fee

Transferase/transferase inhibitor

PDB id: 5fee

Contents

Protein chain

287 a.a.

Ligands

5X4

Waters ×11

References listed in PDB file

Key reference

• Title: Discovery of (r,E)-N-(7-Chloro-1-(1-[4-(Dimethylamino)but-2-Enoyl]azepan-3-Yl)-1h-Benzo[d]imidazol-2-Yl)-2-Methylisonicotinamide (egf816), A novel, Potent, And wt sparing covalent inhibitor of oncogenic (l858r, Ex19del) and resistant (t790m) egfr mutants for the treatment of egfr mutant non-Small-Cell lung cancers.
• Authors: G.Lelais, R.Epple, T.H.Marsilje, Y.O.Long, M.Mcneill, B.Chen, W.Lu, J.Anumolu, S.Badiger, B.Bursulaya, M.Didonato, R.Fong, J.Juarez, J.Li, M.Manuia, D.E.Mason, P.Gordon, T.Groessl, K.Johnson, Y.Jia, S.Kasibhatla, C.Li, J.Isbell, G.Spraggon, S.Bender, P.Y.Michellys.
• Ref.: J Med Chem, 2016, 59, 6671-6689. [DOI no: 10.1021/acs.jmedchem.5b01985]
• PubMed id: 27433829

Abstract

Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach toward the discovery of 47 (EGF816, nazartinib), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through molecular docking studies we converted a mutant-selective high-throughput screening hit (7) into a number of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compounds with good tolerability and efficacy that ultimately led to the selection of 47 as the clinical candidate.