Development of Potent G Protein Pathway-Biased GPR183 Agonists

Bhuskute, K. R.; Manandhar, A.; Kjaer, V. M. S.; Casartelli, F.; Koutsaki, M. I.; Sathyanarayanan, U.; Hjortkilde, E.; Turcio, R.; Rosenkilde, M. M.; Ulven, T.; Ulven, E. R.

doi:10.64898/2026.07.27.740726

bioRxiv · 10.64898/2026.07.27.740726

Development of Potent G Protein Pathway-Biased GPR183 Agonists

Bhuskute, K. R.·Manandhar, A.·Kjaer, V. M. S.·Casartelli, F.·Koutsaki, M. I.·Sathyanarayanan, U.·Hjortkilde, E.·Turcio, R.·Rosenkilde, M. M.·Ulven, T.·Ulven, E. R.

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Abstract

GPR183 is an oxysterol-sensing GPCR predominantly expressed in lymphoid organs and tissues. Activation of the receptor by oxysterol 7,25-OHC leads to Gi protein-mediated signaling as well as {beta}-arrestin2 recruitment. GPR183/oxysterol signaling modulates localization of lymphoid cells, consequently the receptor is associated with several inflammation-associated diseases and is an interesting potential drug target. Previously, we reported the discovery of moderately potent G protein-biased partial agonists for GPR183 from a virtual screening based on the scaffold of the antagonist NIBR189. Herein, we present the detailed structure-activity investigations and optimizations, which led to the identification of full agonists for GPR183 with complete bias for Gi protein signaling and low nanomolar potency, including 63 (TUG-2604) with potency and efficacy similar to 7,25-OHC. Notably, 63 was unable to induce migration of human dendritic cells but inhibited migration induced by 7,25-OHC. This compound will be valuable for further explorations of the signaling-specific function and drug target potential of GPR183.

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Bhuskute, K. R., Manandhar, A., Kjaer, V. M. S., Casartelli, F., Koutsaki, M. I., Sathyanarayanan, U., Hjortkilde, E., Turcio, R., Rosenkilde, M. M., Ulven, T., Ulven, E. R.. 2026-07-30. Development of Potent G Protein Pathway-Biased GPR183 Agonists. https://doi.org/10.64898/2026.07.27.740726

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