Structure-Guided Development of Covalent and Mutant-Selective Pyrazolopyrimidines to Target T790M Drug Resistance in Epidermal Growth Factor Receptor

  • J Med Chem. 2017 Sep 28;60(18):7725-7744. doi: 10.1021/acs.jmedchem.7b00515.
Julian Engel  1 ,  Steven Smith  1 ,  Jonas Lategahn  1 ,  Hannah L Tumbrink  1 ,  Lisa Goebel  1 ,  Christian Becker  1 ,  Elisabeth Hennes  1 ,  Marina Keul  1 ,  Anke Unger  2 ,  Heiko Müller  2 ,  Matthias Baumann  2 ,  Carsten Schultz-Fademrecht  2 ,  Georgia Günther  3 ,  Jan G Hengstler  3 ,  Daniel Rauh  1
Affiliations
  • 1. Faculty of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Straße 4a, D-44227 Dortmund, Germany.
  • 2. Lead Discovery Center GmbH , Otto-Hahn-Straße 15, D-44227 Dortmund, Germany.
  • 3. Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University , D-44139 Dortmund, Germany.
PMID: 28853575 DOI: 10.1021/acs.jmedchem.7b00515
Abstract

Reversible epidermal growth factor receptor (EGFR) inhibitors prompt a beneficial clinical response in Non-Small Cell Lung Cancer patients who harbor activating mutations in EGFR. However, resistance mutations, particularly the gatekeeper mutation T790M, limit this efficacy. Here, we describe a structure-guided development of a series of covalent and mutant-selective EGFR inhibitors that effectively target the T790M mutant. The pyrazolopyrimidine-based core differs structurally from that of aminopyrimidine-based third-generation EGFR inhibitors and therefore constitutes a new set of inhibitors that target this mechanism of drug resistance. These inhibitors exhibited strong inhibitory effects toward EGFR kinase activity and excellent inhibition of cell growth in the drug-resistant cell line H1975, without significantly affecting EGFR wild-type cell lines. Additionally, we present the in vitro ADME/DMPK parameters for a subset of the inhibitors as well as in vivo pharmacokinetics in mice for a candidate with promising activity profile.