Abstract 2291: A novel TGF-βRI inhibitor ASKC852, possessing antitumor and PD-L1 synergistic effect activities

Abstract

Abstract Background: Transforming growth factor-β (TGF-β) plays a significant role in multiple physiological signaling pathways, thus occupies a pivotal position in balancing immunity and antigen tolerance. Activation of TGFβ type I receptor (TGF-βRI) recruits and phosphorylates SMAD transcription factors and promotes EMT gene expression, leading to tumor progression and invasion. Inhibition of this pathway therefore has potential to treat cancer. The preclinical evaluations of a novel TGF-βRI inhibitor ASKC852 is described. Results: ASKC852 has been shown to be a potent and highly selective inhibitor of TGF-βRI. ASKC852 inhibited SMAD phosphorylation in HEK293 cells (IC50 < 0.1 μM), a down-stream PD marker of TGF-β signaling pathway. This compound showed metabolic stability, oral bioavailability in mice and rats, with anti-tumor activity when given alone (TGI: 81.2%) in CT26 colon cancer model. In EMT6 breast carcinoma model, ASKC852 demonstrated significant synergistic effect when combined with a mouse PD-L1 antibody. Greater than 50% p-SMAD inhibition was achieved at low doses in in vivo PD studies. In addition, ASKC852 effectively inhibited tumor metastasis in 4T1-luc2 model. In a 28-days pre-clinical toxicology study, ASKC852 showed no effect on rat cardiovascular system @ 30 mg/kg. Conclusion: Our data demonstrates ASK852 is a potent and highly selective TGF-βRI inhibitor. It effectively blocked the TGF-β-SMAD signal pathway, with anti-tumor effect in syngeneic mouse models. Pharmacokinetic profile and safety properties support ASKC852 as a potential anticancer agent for the clinical treatment of solid tumors. Citation Format: Tingting Song, Min Sun, Hongyu Chen, Xiangyu Fu, Lihong Hu, Shuhua Han, Haijun Tong, Yuanfeng Xia, Jian Zuo, Shaohua Qin, Ying Chen, Charles Ding, Chichung Chan, Shuhui Chen. A novel TGF-βRI inhibitor ASKC852, possessing antitumor and PD-L1 synergistic effect activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2291.