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

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ID: 77191
2017
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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.
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engel2017structureguidedjournal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Julian Engel, Steven Smith, Jonas Lategahn, Hannah L Tumbrink, Lisa Goebel, Christian Becker, Elisabeth Hennes, Marina Keul, Anke Unger, Heiko Müller, Matthias Baumann, Carsten Schultz-Fademrecht, Georgia Günther, Jan G Hengstler, Daniel Rauh
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Journal Journal of medicinal chemistry
Year 2017
DOI
10.1021/acs.jmedchem.7b00515
URL
Keywords
pyrazolopyrimidines 5-aminopyrazoles fused pyrazole derivatives pyrazolopyridines pyrazolotriazines

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