Abstract 4432: A highly differentiated A2AR inhibitor for potential use in cancer therapy

Abstract

Abstract As a potent immunosuppressor adenosine is essential for maintaining tissue homeostasis and preventing an overzealous immune response during inflammation and infection. However, adenosine generated within the tumor microenvironment by the action of ectonucleotides hinders the immune reaction towards cancer cells by signaling through adenosine receptors such as high affinity A2AR expressed on immune cells. Tumors evade the immune response by usurping pathways that negatively regulate normal immune responses. Resistance to inhibition of immune checkpoint targets arises because of an upregulation in the expression of the CD39-CD73 axis and the resulting increase in production of adenosine in the tumor microenvironment. Inhibition of either adenosine generation or signaling by inhibition of A2AR along with other immune activation strategies have been shown to be effective therapeutic approaches. In view of this, we sought to discover and develop novel small molecule inhibitors that dually target A2AR and an immuno-suppressive ligand expressed in the tumor microenvironment. Aurigene’s dual inhibitors exhibit potent inhibition of both A2AR and an immuno-suppressive target of relevance in respective biochemical assays. Potent biochemical activity translated into rescue of chemokines and IL-2 in human PBMCs. Lead compounds exhibited desirable drug-like properties and excellent pharmacokinetic exposure in rodents. In a syngeneic tumor model, lead compounds demonstrated significant tumor growth inhibition. Anti-tumor efficacy correlated well with tumor drug levels and modulation of pharmacodynamic markers. In summary, we have identified first-in-class dual inhibitors with good drug like properties, which showed significant antitumor efficacy. Evaluation of these lead compounds in additional tumor models and in vivo toxicity studies will be presented. Citation Format: Chandregowda Venkateshappa, Kishore Narayanan, Rashmi Nair, Aravind AB, Ramakishore VP Putta, Jwala Nagaraj, Megha Goyal, Vijay Kamal Ahuja, Amith A Dhudashiya, Samiulla DS, Girish Daginakatte, Thomas Antony, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra. A highly differentiated A2AR inhibitor for potential use in cancer therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4432.