2. Academic Validation
  3. Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

  • J Pharmacol Exp Ther. 2016 Sep;358(3):371-86. doi: 10.1124/jpet.116.235333.
Walter Kostich 1,  Brian D Hamman 1,  Yu-Wen Li 1,  Sreenivasulu Naidu 1,  Kumaran Dandapani 1,  Jianlin Feng 1,  Amy Easton 1,  Clotilde Bourin 1,  Kevin Baker 1,  Jason Allen 1,  Katerina Savelieva 1,  Justin V Louis 1,  Manoj Dokania 1,  Saravanan Elavazhagan 1,  Pradeep Vattikundala 1,  Vivek Sharma 1,  Manish Lal Das 1,  Ganesh Shankar 1,  Anoop Kumar 1,  Vinay K Holenarsipur 1,  Michael Gulianello 1,  Ted Molski 1,  Jeffrey M Brown 1,  Martin Lewis 1,  Yanling Huang 1,  Yifeng Lu 1,  Rick Pieschl 1,  Kevin O'Malley 1,  Jonathan Lippy 1,  Amr Nouraldeen 1,  Thomas H Lanthorn 1,  Guilan Ye 1,  Alan Wilson 1,  Anand Balakrishnan 1,  Rex Denton 1,  James E Grace 1,  Kimberley A Lentz 1,  Kenneth S Santone 1,  Yingzhi Bi 1,  Alan Main 1,  Jon Swaffield 1,  Ken Carson 1,  Sandhya Mandlekar 1,  Reeba K Vikramadithyan 1,  Susheel J Nara 1,  Carolyn Dzierba 1,  Joanne Bronson 1,  John E Macor 1,  Robert Zaczek 1,  Ryan Westphal 1,  Laszlo Kiss 1,  Linda Bristow 1,  Charles M Conway 1,  Brian Zambrowicz 2,  Charles F Albright 2
Affiliations

Affiliations

  • 1 Research and Development, Neuroscience Biology (W.K., Y.-W.L., J.F., A.E., C.B., M.G., T.M., J.M.B., M.L., Y.H., Y.L., R.P., R.Z., R.W., L.K., L.B., C.M.C., C.F.A.), Neuroscience Chemistry (C.D., J.B., J.E.M.), Preclinical Candidate Optimization (A.B., J.E.G., K.A.L., K.S.S.), and Discovery Toxicology (R.D.), Bristol-Myers Squibb, Wallingford, Connecticut; Research and Development, Leads Discovery and Optimization, Bristol-Myers Squibb, Pennington, New Jersey (K.O., J.L.); BMS Biocon Research Center, Bangalore, India (K.D., J.V.L., S.N., M.D., S.E., P.V., V.S., M.L.D, G.S., A.K., V.K.H., S.M., R.K.V., S.J.N.); Lexicon Pharmaceuticals, The Woodlands, Texas (B.D.H., K.B., J.A., K.S., A.N., A.W., J.S., B.Z., T.H.L., G.Y.); and Lexicon Pharmaceuticals, Basking Ridge, New Jersey (Y.B., A.M., K.C.).
  • 2 Research and Development, Neuroscience Biology (W.K., Y.-W.L., J.F., A.E., C.B., M.G., T.M., J.M.B., M.L., Y.H., Y.L., R.P., R.Z., R.W., L.K., L.B., C.M.C., C.F.A.), Neuroscience Chemistry (C.D., J.B., J.E.M.), Preclinical Candidate Optimization (A.B., J.E.G., K.A.L., K.S.S.), and Discovery Toxicology (R.D.), Bristol-Myers Squibb, Wallingford, Connecticut; Research and Development, Leads Discovery and Optimization, Bristol-Myers Squibb, Pennington, New Jersey (K.O., J.L.); BMS Biocon Research Center, Bangalore, India (K.D., J.V.L., S.N., M.D., S.E., P.V., V.S., M.L.D, G.S., A.K., V.K.H., S.M., R.K.V., S.J.N.); Lexicon Pharmaceuticals, The Woodlands, Texas (B.D.H., K.B., J.A., K.S., A.N., A.W., J.S., B.Z., T.H.L., G.Y.); and Lexicon Pharmaceuticals, Basking Ridge, New Jersey (Y.B., A.M., K.C.) Charlie.Albright@BMS.com brian.zambrowicz@regeneron.com.
PMID: 27411717 DOI: 10.1124/jpet.116.235333
Abstract

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 Inhibitor and local administration of an AAK1 Inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 Adrenergic Receptor inhibitors, but not Opioid Receptor inhibitors, not only prevented AAK1 Inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.

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