Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic Pain

Journal Article · Thu Jul 10 04:00:00 UTC 2014 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/jm5006429· OSTI ID:1404983

Stachel, Shawn J.; Sanders, John M.; Henze, Darrell A.; Rudd, Mike T.; Su, Hua-Poo; Li, Yiwei; Nanda, Kausik K.; Egbertson, Melissa S.; Manley, Peter J.; Jones, Kristen L. G.; Brnardic, Edward J.; Green, Ahren; Grobler, Jay A.; Hanney, Barbara; Leitl, Michael; Lai, Ming-Tain; Munshi, Vandna; Murphy, Dennis; Rickert, Keith; Riley, Daniel ; Krasowska-Zoladek, Alicja; Daley, Christopher; Zuck, Paul; Kane, Stephanie A.; Bilodeau, Mark T.

We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: INDUSTRY
• OSTI ID: 1404983
• Journal Information: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 13 Vol. 57; ISSN 0022-2623
• Publisher: American Chemical Society (ACS)
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES