Recently, the team of Chiatai Tianqing and WuXi AppTec disclosed for the first time in Bioorganic & Medicinal Chemistry Letters the molecular design thinking of the novel CDK2/4/6 inhibitor - TQB3616 (Culmerciclib) and R&D history.

Small molecule CDK4/6 inhibitors (Palbociclib, Ribociclib, and Abemaciclib) have been successively approved for the treatment of metastatic breast cancer, of which Abemaciclib has shown fewer adverse effects in the clinic attributed to its superior inhibitory activity on CDK4 kinase than on CDK6. Therefore, the research team worked to discover pyrimidine-indazole molecules that are biased to inhibit CDK4 kinase and have some inhibitory activity against CDK2 and CDK6, and TQB3616 was the preferred molecule among such small molecules obtained by SAR screening. It was found that comparing Palbociclib and Abemaciclib, TQB3616 demonstrated different degrees of inhibitory effects on CDK2, CDK4, and CDK6 kinases, and a higher inhibitory capacity for CDK4 kinase [1]. The inhibition of tumor cell proliferation as well as the results of several mouse transplantation tumor model studies verified its anti-tumor activity. In addition, the results showed [1] that the inhibition of CDK2 by TQB3616 was further enhanced compared to Abemaciclib, and its enhanced CDK2 and CDK4 inhibitory activity may help to overcome the resistance problem of the current CDK4/6 inhibitors in the clinic.

With the performance of its preclinical study data, TQB3616 will start its first Phase I clinical study in China in 2019, and several Phase III clinical trials (NCT05375461, NCT05365178) of its combination with fulvestrant for the treatment of HR+/HER-breast cancer have completed enrollment, and the results of the trials will be unveiled soon. A Phase III clinical study of postoperative adjuvant therapy is recruiting patients nationwide (NCT05780567).

TQB3616, a novel CDK2/4/6 inhibitor optimized for activity and selectivity, will bring a new treatment option for HR+/HER- advanced breast cancer patients. We look forward to the early launch of TQB3616 to benefit more breast cancer patients.

https://mp.weixin.qq.com/s?__biz=MzA5NDE4ODc2MA==&mid=2650366801&idx=1&sn=2627a7bb1cdd43ea875da70d25d6afc4&chksm=885fa6e6bf282ff048077c4fa3297fce0b8fb15cc3b30f50c3344e87ace57b760ae75f3bd5ba&mpshare=1&scene=1&srcid=0522H16zmgOlXVcxtLKFZsav&sharer_shareinfo=9692f734a865ae7f8421b27f2ba0e68d&sharer_shareinfo_first=9692f734a865ae7f8421b27f2ba0e68d#rd