Structural characterization of nonactive site, TrkA-selective kinase inhibitors
- Merck & Co. Inc., West Point, PA (United States)
- Merck & Co. Inc., West Point, PA (United States); MedImmune, Gaithersburg, MD (United States)
- Merck & Co. Inc., West Point, PA (United States); Sanofi Pasteur, Swiftwater, PA (United States)
- Merck & Co. Inc., West Point, PA (United States); Spectrix Analytic Services, LLC., Princeton, NJ (United States)
- Merck & Co. Inc., West Point, PA (United States); Bristol-Myers Squibb, Pennington, NJ (United States)
- Merck & Co. Inc., West Point, PA (United States); Janssen R&D LLC., Spring House, PA (United States)
- Merck & Co. Inc., West Point, PA (United States); LabConnect, LLC., Seattle, WA (United States)
- Merck & Co. Inc., West Point, PA (United States); Novartis Inst. of BioMedical Research, Cambridge, MA (United States)
- Merck & Co. Inc., West Point, PA (United States); Tarveda Therapeutics, Watertown, MA (United States)
Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosin-related kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief. Here, we describe the identification of TrkA-specific inhibitors and the structural basis for their selectivity over other Trk family kinases. The X-ray structures reveal a binding site outside the kinase active site that uses residues from the kinase domain and the juxtamembrane region. Three modes of binding with the juxtamembrane region are characterized through a series of ligand-bound complexes. The structures indicate a critical pharmacophore on the compounds that leads to the distinct binding modes. The mode of interaction can allow TrkA selectivity over TrkB and TrkC or promiscuous, pan-Trk inhibition. This finding highlights the difficulty in characterizing the structure-activity relationship of a chemical series in the absence of structural information because of substantial differences in the interacting residues. Furthermore, these structures illustrate the flexibility of binding to sequences outside of—but adjacent to—the kinase domain of TrkA. This knowledge allows development of compounds with specificity for TrkA or the family of Trk proteins.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division
- Grant/Contract Number:
- AC02-06CH11357
- OSTI ID:
- 1343145
- Journal Information:
- Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, Issue 3; ISSN 0027-8424
- Publisher:
- National Academy of SciencesCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Web of Science
Synthetic inhibitor leads of human tropomyosin receptor kinase A ( h TrkA)
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journal | January 2020 |
Structural basis of the transmembrane domain dimerization and rotation in the activation mechanism of the TRKA receptor by nerve growth factor
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journal | December 2019 |
Structural Basis of the Transmembrane Domain Dimerization in the Activation Mechanism of TrkA by NGF | posted_content | October 2019 |
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