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An isoform-selective inhibitor of tropomyosin receptor kinase A behaves as molecular glue
Institution:1. Kissei Pharmaceutical Inc., Azumino City, Nagano Pref., Japan;2. Graduate School of Science, Osaka Prefecture University, Osaka, Japan;3. Carna Biosciences, Inc., Kobe, Japan;1. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemistry Drug Development, School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, China;2. Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, 510530, China;1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA;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. Blood Brain Barrier Laboratory (LBHE), University of Artois, UR2465, F-62300, Lens, France;1. Anteo Diagnostics, Eight Mile Plains, 4113 QLD, Australia;2. Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, 4072 QLD, Australia;3. Centre for Advanced Imaging, University of Queensland, Brisbane, 4072 QLD, Australia
Abstract:The production of TrkA-selective inhibitors is considerably difficult because the kinase domains of TrkA and its isoforms TrkB/C have highly homologous amino acid sequences. Here we describe the structural basis for the acquisition of selectivity for a isoform-selective TrkA inhibitor, namely compound V1. The X-ray structure revealed that V1 acts as a molecular glue to stabilize the symmetrical dimer of the TrkA kinase domains. V1 binds to the ATP-binding site and simultaneously engages in the dimeric interface of TrkA. The region of the dimeric interface in TrkA is not conserved in TrkB/C; thus, dimer formation may be a novel mechanism for the production of selective TrkA inhibitors. The biochemical and biophysical assay results confirmed that V1 selectively inhibited TrkA and induced the dimer formation of TrkA, but not TrkB. The binding pocket at the TrkA dimer interface can be used for the production of new isoform-selective TrkA inhibitors.
Keywords:TrkA kinase  Crystal structure  Tyrosine kinase inhibitor  Molecule glue  Small molecule ligand interface stabilizers  Symmetric dimer
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