Property- and structure-guided discovery of a tetrahydroindazole series of interleukin-2 inducible T-cell kinase inhibitors

  • J Med Chem. 2014 Jul 10;57(13):5714-27. doi: 10.1021/jm500550e.
Jason D Burch  1 ,  Kevin Lau ,  John J Barker ,  Fred Brookfield ,  Yong Chen ,  Yuan Chen ,  Charles Eigenbrot ,  Claire Ellebrandt ,  M Hicham A Ismaili ,  Adam Johnson ,  Daniel Kordt ,  Colin H MacKinnon ,  Paul A McEwan ,  Daniel F Ortwine ,  Daniel B Stein ,  Xiaolu Wang ,  Dirk Winkler ,  Po-Wai Yuen ,  Yamin Zhang ,  Ali A Zarrin ,  Zhonghua Pei
Affiliations
  • 1. Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
PMID: 24918870 DOI: 10.1021/jm500550e
Abstract

Interleukin-2 inducible T-cell kinase (Itk), a member of the Tec family of tyrosine Kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as Asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective Itk inhibitor (GNE-9822) with good ADME properties in preclinical species.

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