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Structural characterization of nonactive site, TrkA-selective kinase inhibitors

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
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  1. Merck & Co. Inc., West Point, PA (United States)
  2. Merck & Co. Inc., West Point, PA (United States); MedImmune, Gaithersburg, MD (United States)
  3. Merck & Co. Inc., West Point, PA (United States); Sanofi Pasteur, Swiftwater, PA (United States)
  4. Merck & Co. Inc., West Point, PA (United States); Spectrix Analytic Services, LLC., Princeton, NJ (United States)
  5. Merck & Co. Inc., West Point, PA (United States); Bristol-Myers Squibb, Pennington, NJ (United States)
  6. Merck & Co. Inc., West Point, PA (United States); Janssen R&D LLC., Spring House, PA (United States)
  7. Merck & Co. Inc., West Point, PA (United States); LabConnect, LLC., Seattle, WA (United States)
  8. Merck & Co. Inc., West Point, PA (United States); Novartis Inst. of BioMedical Research, Cambridge, MA (United States)
  9. Merck & Co. Inc., West Point, PA (United States); Tarveda Therapeutics, Watertown, MA (United States)
+ Show Author Affiliations
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) (SC-22). 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, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 3 Vol. 114; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (37)

The effect of systemically administered recombinant human nerve growth factor in healthy human subjects journal August 1994
Structural biology of protein tyrosine kinases journal October 2006
The trk proto-oncogene encodes a receptor for nerve growth factor journal April 1991
Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity journal September 1994
Trk receptors use redundant signal transduction pathways involving SHC and PLC-γ1 to mediate NGF responses journal March 1994
The Structural Basis for Autoinhibition of FLT3 by the Juxtamembrane Domain journal January 2004
The Crystal Structures of TrkA and TrkB Suggest Key Regions for Achieving Selective Inhibition journal October 2012
The Juxtamembrane Region of the EGF Receptor Functions as an Activation Domain journal June 2009
Opioids in chronic non-cancer pain: systematic review of efficacy and safety journal January 2004
Novel class of pain drugs based on antagonism of NGF journal February 2006
Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor journal March 2016
( R )-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors journal March 2015
Novel Benzimidazole Inhibitors Bind to a Unique Site in the Kinesin Spindle Protein Motor Domain journal September 2010
Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic Pain journal June 2014
Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis journal August 1996
Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family journal November 2012
Tanezumab for the Treatment of Pain from Osteoarthritis of the Knee journal October 2010
Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors journal September 2012
Identification and biochemical characterization of p70TRK, product of the human TRK oncogene. journal October 1987
COSMIC: exploring the world's knowledge of somatic mutations in human cancer journal October 2014
NGF as a mediator of inflammatory pain journal March 1996
The Trk Family of Tyrosine Kinases: Receptors for NGF-related Neurotrophins journal January 1992
Refinement of severely incomplete structures with maximum likelihood in BUSTER–TNT journal November 2004
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Features and development of Coot journal March 2010
Data processing and analysis with the autoPROC toolbox journal March 2011
Probing the binding mechanism and affinity of tanezumab, a recombinant humanized anti-NGF monoclonal antibody, using a repertoire of biosensors journal August 2008
The Protein Kinase Complement of the Human Genome journal December 2002
The trk proto-oncogene product: a signal transducing receptor for nerve growth factor journal April 1991
Molecular and biochemical characterization of the human trk proto-oncogene. journal January 1989
NEUROTROPHINS: Mediators and Modulators of Pain journal July 2006
TRKing Down an Old Oncogene in a New Era of Targeted Therapy journal December 2014
Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer journal November 2015
Trk kinase inhibitors as new treatments for cancer and pain journal March 2009
The potential of neurotrophic tyrosine kinase (NTRK) inhibitors for treating lung cancer journal February 2016
Targeting Nerve Growth Factor in Pain: What is the Therapeutic Potential? journal January 2008
Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases journal April 2014

Cited By (3)

Synthetic inhibitor leads of human tropomyosin receptor kinase A ( h TrkA) journal January 2020
Structural basis of the transmembrane domain dimerization and rotation in the activation mechanism of the TRKA receptor by nerve growth factor 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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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
TrkA
inhibition
kinase
pain
selectivity