Exploring the Potential of RET Kinase Inhibition for Irritable Bowel Syndrome: A Preclinical Investigation in Rodent Models of Colonic Hypersensitivity.

Autor:	Russell JP; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)., Mohammadi E; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)., Ligon CO; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)., Johnson AC; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)., Gershon MD; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)., Rao M; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)., Shen Y; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)., Chan CC; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)., Eidam HS; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)., DeMartino MP; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)., Cheung M; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)., Oliff AI; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)., Kumar S; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)., Greenwood-Van Meerveld B; Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.) beverley-greenwood@ouhsc.edu.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2019 Feb; Vol. 368 (2), pp. 299-307. Date of Electronic Publication: 2018 Nov 09.
DOI:	10.1124/jpet.118.252973
Abstrakt:	Abdominal pain represents a significant complaint in patients with irritable bowel syndrome (IBS). While the etiology of IBS is incompletely understood, prior exposure to gastrointestinal inflammation or psychologic stress is frequently associated with the development of symptoms. Inflammation or stress-induced expression of growth factors or cytokines may contribute to the pathophysiology of IBS. Here, we aimed to investigate the therapeutic potential of inhibiting the receptor of glial cell line-derived neurotrophic factor, rearranged during transfection (RET), in experimental models of inflammation and stress-induced visceral hypersensitivity resembling IBS sequelae. In RET-cyan fluorescent protein [(CFP) Ret CFP/+ ] mice, thoracic and lumbosacral dorsal root ganglia were shown to express RET, which colocalized with calcitonin gene-related peptide. To understand the role of RET in visceral nociception, we employed GSK3179106 as a potent, selective, and gut-restricted RET kinase inhibitor. Colonic hyperalgesia, quantified as exaggerated visceromotor response to graded pressures (0-60 mm Hg) of isobaric colorectal distension (CRD), was produced in multiple rat models induced 1) by colonic irritation, 2) following acute colonic inflammation, 3) by adulthood stress, and 4) by early life stress. In all the rat models, RET inhibition with GSK3179106 attenuated the number of abdominal contractions induced by CRD. Our findings identify a role for RET in visceral nociception. Inhibition of RET kinase with a potent, selective, and gut-restricted small molecule may represent a novel therapeutic strategy for the treatment of IBS through the attenuation of post-inflammatory and stress-induced visceral hypersensitivity. (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu