Abstract 504: BPI-472372: a potent and orally bioavailable small molecule inhibitor of CD73 for cancer immunotherapy

Abstract

Abstract CD73, also known as ecto-5'-nucleotidase, plays a major role in converting extracellular adenosine monophosphate (AMP) to immunosuppressive adenosine. It is frequently overexpressed across a variety of cancers. High adenosine level in the tumor microenvironment, predominantly signaling through the A2a/A2b receptors, suppresses innate and adaptive immune responses and mediates tumor immune evasion. CD73 overexpression is correlated with poor prognosis in several tumor types. Inhibition of CD73 to reduce adenosine production is a promising therapeutic approach for the treatment of cancer. Both monoclonal antibodies and small molecule inhibitors are being explored to target CD73. Small molecule CD73 inhibitor with good balance of activity and ADME properties are rare. Here we present BPI-472372, a potent, selective, and orally bioavailable small molecule CD73 inhibitor. It strongly inhibits both soluble and cell-bound CD73, with no off-target activity on other related nucleotidases (NTPDases 1/2/3/5), nor on a large panel of enzymes, receptors, and ion channels. BPI-472372 reversed AMP-induced CD4+ T cell suppression in a dose-dependent manner. In vivo, BPI-472372 exhibited anti-tumor effect in MC38 syngeneic mouse model with no visible adverse effect. Moreover, enhanced tumor growth inhibition activity was observed when BPI-472372 was combined with durvalumab (anti-PD-L1) in humanized PD-L1 syngeneic MC38 model. BPI-472372 exhibited desirable drug-like properties including high permeability, low hepatocytes clearance, and adequate oral exposure across multiple pre-clinical species. GLP toxicity study indicated that BPI-472372 was well tolerated at high dose following 4 weeks repeated administration in both mouse and dog. Taken together, BPI-472372 is a potent and orally bioavailable small molecule CD73 inhibitor with single agent anti-tumor efficacy, favorable ADME properties, and a wide therapeutic index. Citation Format: Han Han, Xiaofeng Yang, Ying Zhao, Jin Wang, Xiang Yang, Xuepeng Ju, Jiayu Zhao, Zhengyao Zou, Haibo Chen, Xiaoyun Liu, Jing Guo, Cheng Yang, Hong Lan, Hao Wu, Lieming Ding, Jiabing Wang. BPI-472372: a potent and orally bioavailable small molecule inhibitor of CD73 for cancer immunotherapy [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 504.