Abstract 5778: Preclinical evaluation of TQB3616, a highly potent and selective small-molecule CDK4/6 inhibitor

Abstract Objective: The G1 restriction point is critical for regulating the cell cycle and is controlled by the retinoblastoma protein (Rb) pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). Selective CDK4/6 inhibitors, such as palbociclib and ribociclib have been approved by US FDA in combination with letrozole to treat patients with HR+/Her2- breast cancer, and selective CDK4/6 inhibitor LY2835219 is in Phase 3 trials for the same and related indications. Here, we disclose TQB3616 for the first time, a novel selective, potent, oral inhibitor of CDK4/6. Method: The anti-proliferative activity of TQB3616 was evaluated in a panel of 18 Rb-proficient cell lines in a 72-hour viability assay. Daily oral administration was used to evaluate in vivo antitumor activity of TQB3616 in the MCF-7 cell-derived xenograft (CDX) breast cancer model. Effect on CDK4/6-cyclin D1-Rb signaling was assessed by western blot analysis of downstream effector protein p-Rb. In vivo antitumor activity of TQB3616 was also tested in a patient-derived xenograft (PDX) lung cancer model LU-01-0393. Result: TQB3616 displayed potent anti-proliferative activity in 8 of 18 Rb-proficient cancer cell lines (>50% inhibition at 0.3 µM). Inhibition of p-Rb in the tumor samples was verified by western blot analysis. TQB3616 showed in vivo antitumor activity in the MCF-7 CDX model with TGI of 60% @7.5 mpk and 93% @15 mpk, better than palbociclib (TGI = 52% @20 mpk, 80% @40 mpk) and LY2835219 (TGI = 45% @7.5 mpk, 76% @15 mpk). TQB3616 also showed good in vivo antitumor activity in the LU-01-0393 lung cancer PDX model with 65% of TGI @35 mpk. Conclusion: TQB3616 is a potent and selective CDK4/6 inhibitor and shows excellent antitumor activity in preclinical tumor models. These results warrant TQB3616 going to the clinic for exploration of its potential for treating HR+/Her2-/Rb+ breast cancer as well as other Rb+ cancer types. Citation Format: Xu Zhaobing, Hu Lihong, Liu Yingchun, Charles Z. Ding, Xiaoyu Zhu, Chen Chen, Yusong Zhu, Jiahu Wu, Dongdong Wu, Shuhui Chen, Xiquan Zhang, Ling Yang, Xin Tian. Preclinical evaluation of TQB3616, a highly potent and selective small-molecule CDK4/6 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5778.