Here, we identify a subset of vascular pericytes, defined by expression of platelet-derived growth factor receptor beta (PDGFR-β) and G-protein-coupled receptor 91 (GPR91), that promote tumorigenesis and tyrosine kinase inhibitors (TKIs) resistance by functioning as the primary methionine source for cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC). Tumor-cell-derived succinate binds to GPR91 on pericyte to activate autophagy for methionine production. CSCs use methionine to create stabilizing N6-methyladenosine in ATPase-family-AAA-domain-containing 2 (ATAD2) mRNA, and the resulting ATAD2 protein complexes with SRY-box transcription factor 9 to assemble super enhancers and thereby dictate its target genes that feature prominently in CSCs. Targeting PDGFR-β+GPR91+ pericytes with specific GRP91 antagonists reduce intratumoral methionine level, eliminate CSCs, and enhance TKIs sensitivity. These results unraveled the mechanisms by which PDGFR-β+GPR91+ pericytes provide supportive niche for CSCs and could be used to develop targets for treating ccRCC.

01 Mar 2024·Journal of Pharmacology and Experimental Therapeutics

12-(S)-Hydroxyeicosatetraenoic Acid and GPR31 Signaling in Spinal Cord in Neuropathic Pain

Article

Author: Lauro, Filomena ; Salvemini, Daniela ; Zhang, Jinsong ; Olayide, Israel ; Giancotti, Luigino Antonio ; Arnatt, Christopher Kent

Neuropathic pain is a pressing unmet medical need requiring novel nonopioid-based therapeutic approaches. Using unbiased transcriptomic analysis, we found that the expression of Gpr31, a G protein-coupled receptor, increased in the dorsal horn of the spinal cord in rats with traumatic nerve injury-induced neuropathic pain. Daily intrathecal injections of siGpr31 reversed behavioral hypersensitivities in a time-dependent manner. GPR31, a Gα _i protein-coupled receptor, has recently been cloned and is a receptor for 12-(S)-hydroxyeicosatetraenoic acid [12-(S)-HETE]. The lack of commercially available GPR31 antagonists has hampered the understanding of this receptor in pathophysiological states, including pain. To investigate this, our first approach was to identify novel GPR31 antagonists. Using a multidisciplinary approach, including in silico modeling, we identified the first highly potent and selective small-molecule GPR31 antagonist, SAH2. Here, we characterize the pharmacological activity in well-described models of neuropathic pain in rodents and provide evidence that 12-(S)-HETE/GPR31-dependent behavioral hypersensitivities are mediated through mitogen-activated protein kinase (MAPK) activation in the spinal cord. Our studies provide the pharmacological rationale for investigating contributions of GPR31 along the pain neuroaxis and the development of nonopioid GPR31-targeted strategies. SIGNIFICANCE STATEMENT: We have identified the first highly selective GPR31 antagonist. Using this antagonist, we have demonstrated that GPR31 signaling in the spinal cord is pronociceptive and MAPK pathways provided signaling mechanisms downstream of GPR31 activation in these processes.

12 Jan 2023·ACS Medicinal Chemistry Letters

Thienopyrimidine Derivatives as GPR55 Receptor Antagonists: Insight into Structure–Activity Relationship

Article

Author: Sayed, Sommayah S. ; Morales, Paula ; Reggio, Patricia H. ; Abood, Mary E. ; Fernández-Ruiz, Javier ; Gómez-Cañas, María ; Jagerovic, Nadine ; Hurst, Dow P. ; Zhao, Pingwei ; Figuerola-Asencio, Laura ; Colón, Katsuya L. ; Croatt, Mitchell P.

GPR55 is an orphan G-protein coupled receptor involved in various pathophysiological conditions. However, there are only a few noncannabinoid GPR55 ligands reported so far. The lack of potent and selective GPR55 ligands precludes a deep exploration of this receptor. The studies presented here focused on a thienopyrimidine scaffold based on the GPR55 antagonist ML192, previously discovered by high-throughput screening. The GPR55 activities of the new synthesized compounds were assessed using β-arrestin recruitment assays in Chinese hamster ovary cells overexpressing human GPR55. Some derivatives were identified as GPR55 antagonists with functional efficacy and selectivity versus CB1 and CB2 cannabinoid receptors.

100 Deals associated with GPR91 Antagonists(Impetis Biosciences Ltd.)

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis	Preclinical	IN	Impetis Biosciences Ltd.	30 Nov 2022
Neovascularization, Pathologic	Preclinical	IN	Impetis Biosciences Ltd.	30 Nov 2022
stress oxidative	Preclinical	IN	Impetis Biosciences Ltd.	30 Nov 2022

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