Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application

  • J Med Chem. 2019 Feb 28;62(4):1731-1760. doi: 10.1021/acs.jmedchem.8b01092.
Wei Yan  1 ,  Naga Rajiv Lakkaniga  1 ,  Francesca Carlomagno  2  3 ,  Massimo Santoro  2 ,  Neil Q McDonald  4  5 ,  Fengping Lv  1 ,  Naresh Gunaganti  1 ,  Brendan Frett  1 ,  Hong-Yu Li  1
Affiliations
  • 1. Department of Pharmaceutical Sciences, College of Pharmacy , University of Arkansas for Medical Sciences , Little Rock , Arkansas 72205 , United States.
  • 2. Dipartimento di Medicina Molecolare e Biotecnologie Mediche , Università Federico II , Via S Pansini 5 , 80131 Naples , Italy.
  • 3. Istituto di Endocrinologia e Oncologia Sperimentale del CNR , Via S Pansini 5 , 80131 Naples , Italy.
  • 4. Signaling and Structural Biology Laboratory , The Francis Crick Institute , London NW1 1AT , U.K.
  • 5. Institute of Structural and Molecular Biology, Department of Biological Sciences , Birkbeck College , Malet Street , London WC1E 7HX , U.K.
PMID: 30188734 DOI: 10.1021/acs.jmedchem.8b01092
Abstract

The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (Trk) cancers are diagnosed, with the majority of cases exhibiting a Trk genomic rearrangement. In this Perspective, we discuss current development and clinical applications for Trk precision medicine by providing the following: (1) the biological background and significance of the Trk kinase family, (2) a compilation of known Trk inhibitors and analysis of their cocrystal structures, (3) an overview of Trk clinical trials, and (4) future perspectives for drug discovery and development of Trk inhibitors.