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Last update 08 May 2025

P2RY11

Last update 08 May 2025

Basic Info

Synonyms

P2RY11, P2Y purinoceptor 11, P2Y11

+ [2]

Introduction

Receptor for ATP and ADP coupled to G-proteins that activate both phosphatidylinositol-calcium and adenylyl cyclase second messenger systems. Not activated by UTP or UDP.

Drugs associated with P2RY11

SSA-37A

Target

P2RY11 x P2Y1

Mechanism

P2RY11 agonists [+1]

Active Org.-

Originator Org.

Bar-Ilan University

Active Indication-

Inactive Indication

Alzheimer Disease

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with P2RY11

100 Translational Medicine associated with P2RY11

0 Patents (Medical) associated with P2RY11

154

Literatures (Medical) associated with P2RY11

23 Apr 2025·Journal of Leukocyte Biology

Noncanonical NF-κB signaling in dendritic cells is required for ATP-driven indoleamine 2,3-dioxygenase 1 induction through P2Y11 receptor

Article

Author: Salvestrini, Valentina ; Di Virgilio, Francesco ; Pegoraro, Anna ; Ocadlikova, Darina ; Cavo, Michele ; Vitali, Letizia ; Forte, Dorian ; Trabanelli, Sara ; Jandus, Camilla ; Campazzi, Emma ; Ciciarello, Marilena ; Curti, Antonio ; Adinolfi, Elena ; Fiordi, Benedetta ; Cipollitta, Serenella C

AbstractExtracellular ATP released from dying cells, including tumor cells, is a key mediator of inflammation and tolerance by binding to purinergic receptors on dendritic cells (DCs), resulting in inflammasome activation (via P2X7R), DC maturation (via P2Y11R), and indoleamine-2,3-dioxygenase 1 upregulation. However, the regulation of ATP-driven Indoleamine-2,3-dioxygenase 1 expression in human DCs has been poorly investigated. In this work, we aimed to investigate the ATP-driven molecular regulation of indoleamine-2,3-dioxygenase 1 expression via purinergic receptors and to provide an in-depth characterization of ATP-driven T regulatory cells induced by indoleamine-2,3-dioxygenase 1-expressing DCs. We identified P2Y11R as being responsible for ATP-driven indoleamine-2,3-dioxygenase 1 upregulation, and noncanonical NF-kB as a molecular pathway associated with ATP-dependent indoleamine-2,3-dioxygenase 1 induction through P2Y11R. Then, we investigated—but did not confirm—an involvement of inflammasome machinery through P2X7R in indoleamine-2,3-dioxygenase 1 upregulation. Finally, we evaluated the role of ATP catabolism via ATP ectonucleotidases, i.e. CD39 and CD73 and its main product adenosine, in regulating the generation of indoleamine-2,3-dioxygenase 1-driven T regulatory cells. We found that ATP-driven indoleamine-2,3-dioxygenase 1 upregulation is associated with CD73 upregulation and adenosine production. Additionally, ATP-treated indoleamine-2,3-dioxygenase 1-positive mature DCs induce PD-1-expressing bona fide suppressive T regulatory cells via adenosine A2AR. Collectively, a more in-depth understanding of ATP-driven immune-regulatory mechanisms through indoleamine-2,3-dioxygenase 1 regulation in human DCs leading to the induction of T regulatory cells can have clinical implications for the development of indoleamine-2,3-dioxygenase 1 inhibitors in cancer patients, especially in combination with immunotherapy such as an anti-CD73 or adenosine receptor agonist and immunogenic chemotherapy.

01 Dec 2024·Cellular and Molecular Life Sciences

Crosstalk between purinergic receptor P2Y11 and chemokine receptor CXCR7 is regulated by CXCR4 in human macrophages

Article

Author: Klaver, Dominik ; Thurnher, Martin ; Amato, Marco ; Frena, Beatrice ; Gander, Hubert

AbstractP2Y11 is a G protein-coupled ATP receptor that activates IL-1 receptor (IL-1R) in a cyclic AMP dependent manner. In human macrophages, P2Y11/IL-1R crosstalk with CCL20 as a prime target is controlled by phosphodiesterase 4 (PDE4), which mediates breakdown of cyclic AMP. Here, we used gene expression analysis to identify activation of CXCR4 and CXCR7 as a hallmark of P2Y11 signaling. We found that PDE4 inhibition with rolipram boosts P2Y11/IL-1R-induced upregulation of CXCR7 expression and CCL20 production in an epidermal growth factor receptor dependent manner. Using an astrocytoma cell line, naturally expressing CXCR7 but lacking CXCR4, P2Y11/IL-1R activation effectively induced and CXCR7 agonist TC14012 enhanced CCL20 production even in the absence of PDE4 inhibition. Moreover, CXCR7 depletion by RNA interference suppressed CCL20 production. In macrophages, the simultaneous activation of P2Y11 and CXCR7 by their respective agonists was sufficient to induce CCL20 production with no need of PDE4 inhibition, as CXCR7 activation increased its own and eliminated CXCR4 expression. Finally, analysis of multiple CCL chemokines in the macrophage secretome revealed that CXCR4 inactivation and CXCR7 activation selectively enhanced P2Y11/IL-1R-mediated secretion of CCL20. Altogether, our data establish CXCR7 as an integral component of the P2Y11/IL-1R-initiated signaling cascade and CXCR4-associated PDE4 as a regulatory checkpoint.

01 Oct 2024·Molecular Cancer Therapeutics

Characterization of AB598, a CD39 Enzymatic Inhibitory Antibody for the Treatment of Solid Tumors

Article

Author: Parashar, Kaustubh ; Zhao, Xiaoning ; Singh, Hema ; Kaplan, Angelo ; Walters, Matthew J. ; Stagnaro, Carlo E. ; Bowman, Christine E. ; Clor, Julie ; Singh, Jaskirat ; Guan, Yihong ; Sathishkumar, Pavithra ; Kushwaha, Ritu ; Fernandez-Salas, Ester ; Vani, Urvi ; Juat, Damie J. ; Seitz, Lisa ; Talukdar, Priyanka ; Anderson, Amy E. ; Jin, Ke ; Chen, Ada ; Walker, Nigel P.C.

AbstractAB598 is a CD39 inhibitory antibody being pursued for the treatment of solid tumors in combination with chemotherapy and immunotherapy. CD39 metabolizes extracellular adenosine triphosphate (eATP), an alarmin capable of promoting antitumor immune responses, into adenosine, an immuno-inhibitory metabolite. By inhibiting CD39, the consumption of eATP is reduced, resulting in a proinflammatory milieu in which eATP can activate myeloid cells to promote antitumor immunity. The preclinical characterization of AB598 provides a mechanistic rationale for combining AB598 with chemotherapy in the clinic. Chemotherapy can induce ATP release from tumor cells and, when preserved by AB598, both chemotherapy-induced eATP and exogenously added ATP promote the function of monocyte-derived dendritic cells via P2Y11 signaling. Inhibition of CD39 in the presence of ATP can promote inflammasome activation in in vitro-derived macrophages, an effect mediated by P2X7. In a MOLP8 murine xenograft model, AB598 results in full inhibition of intratumoral CD39 enzymatic activity, an increase in intratumoral ATP, a decrease of extracellular CD39 on tumor cells, and ultimately, control of tumor growth. In cynomolgus monkeys, systemic dosing of AB598 results in effective enzymatic inhibition in tissues, full peripheral and tissue target engagement, and a reduction in cell surface CD39 both in tissues and in the periphery. Taken together, these data support a promising therapeutic strategy of harnessing the eATP generated by standard-of-care chemotherapies to prime the tumor microenvironment for a productive antitumor immune response.

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P2RY11

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