4PMS

The structure of TrkA kinase bound to the inhibitor 4-naphthalen-1-yl-1-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid

Summary for 4PMS

• Entry DOI: 10.2210/pdb4pms/pdb
• Related: 4PMM 4PMP 4PMT
• Descriptor: High affinity nerve growth factor receptor, 4-(naphthalen-1-yl)-1-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P04629
• Total number of polymer chains: 1
• Total formula weight: 33891.41

Authors

Su, H.P. (deposition date: 2014-05-22, release date: 2014-06-18, Last modification date: 2023-12-27)

Primary citation

Stachel, S.J.,Sanders, J.M.,Henze, D.A.,Rudd, M.T.,Su, H.P.,Li, Y.,Nanda, K.K.,Egbertson, M.S.,Manley, P.J.,Jones, K.L.,Brnardic, E.J.,Green, A.,Grobler, J.A.,Hanney, B.,Leitl, M.,Lai, M.T.,Munshi, V.,Murphy, D.,Rickert, K.,Riley, D.,Krasowska-Zoladek, A.,Daley, C.,Zuck, P.,Kane, S.A.,Bilodeau, M.T.
Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.
J.Med.Chem., 57:5800-5816, 2014

PubMed Abstract: 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.

PubMed: 24914455
DOI: 10.1021/jm5006429

Experimental method

X-RAY DIFFRACTION (2.8 Å)