Abstract 4086: Preclinical evaluation of pharmacokinetics, pharmacodynamics and efficacy of the dual CD73-A2AR Inhibitors

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 ecto-nucleotidases including CD73 hinders the immune reaction towards cancer cells by signaling through adenosine receptors such as high affinity A2AR expressed on immune cells. Inhibitions of either adenosine generation or signaling by inhibiting CD73 or A2AR have been shown to be effective therapeutic approaches. Interestingly, the co-blockade of CD73 and A2AR results in a more pronounced anti-tumor activity than blockade of either, likely due to increased CD73 expression upon A2AR inhibition and compensatory activity of other adenosine receptors such as A2BR. In view of this, we sought to discover and develop small molecule inhibitors that dually target CD73 and A2AR with oral bioavailability for ease of administration and use in combination with other anti-cancer therapies. Aurigene’s dual inhibitors exhibit potent inhibition of both A2AR and CD73 in respective biochemical and cellular assays. High potency translated into rescue of NECA or AMP induced repression of IFNΥ and IL2 in human PBMCs. Lead compounds exhibited desirable drug-like properties including solubility, permeability, lack of CYP inhibition, and pharmacokinetic exposure. In Syngeneic tumour model, treatment with lead compounds resulted in significant tumour growth inhibition while correlating well with tumour 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 tumour models and in vivo toxicity studies is currently under way. Citation Format: Dinesh Chikkanna, Kishore Narayanan, Sunil Panigrahi, Garima Priyadarshini, Megha Goyal, Jiju Mani, DS Samiulla, Sagar dadhania, AB Aravind, Girish Daginakatte, Thomas Anthony, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra. Preclinical evaluation of pharmacokinetics, pharmacodynamics and efficacy of the dual CD73-A2AR Inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4086.