Identification of two novel RET kinase inhibitors through MCR-based drug discovery: Design, synthesis and evaluation

Brendan Frett, Marialuisa Moccia, Francesca Carlomagno, Massimo Santoro, Hong Yu Li

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

From an MCR fragment library, two novel chemical series have been developed as inhibitors of RET, which is a kinase involved in the pathology of medullary thyroid cancer (MTC). Structure activity relationship studies (SAR) identified two sub-micromolar tractable leads, 6g and 13g. 6g was confirmed to be a Type-II RET inhibitor. 13g and 6g inhibited RET in cells transformed by RET/C634. A RET DFG-out homology model was established and utilized to predict Type-II inhibitor binding modes.

Original languageEnglish (US)
Pages (from-to)714-723
Number of pages10
JournalEuropean journal of medicinal chemistry
Volume86
DOIs
StatePublished - Oct 30 2014

Keywords

  • Kinase
  • Lead discovery
  • MCR
  • Medicinal chemistry
  • RET
  • Targeted therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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