Rearranged during transfection (RET) kinase is a neuronal growth factor receptor tyrosine kinase that is activated upon binding to one of four neurotrophic factors. RET activity is critical for the development of the ENS (enteric nervous system), the kidney, and spermatogenesis. Inhibition of RET in the ENS represents a novel therapeutic strategy for the normalization of neuronal function and the symptoms of IBS (irritable bowel syndrome) patients. GSK3179106 is a potent, selective, and gut-restricted pyridone hinge binder small molecule RET kinase inhibitor with an IC50 of 0.3 nM and is efficacious in vivo. It presents IC50s of 0.4 and 11 nM in the biochemical assay and cellular assay, respectively. GSK3179106 competely binds to the kinobeads with pKdapp of 7.9 or Kd of 0.02 μM. GSK3179106 dosed orally at 10 mg/kg (n = 7) for 3.5 days BID reduced the visceromotor response to colorectal distension in comparison to rats given an acetic acid enema and dosed with vehicle. GSK3179106 was further progressed to rodent safety studies and found to have a favorable safety profile to support clinical testing[1].
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