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

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

Affiliation

  • 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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