Abstract 5315: BPI-28592, a next-generation TRK kinase inhibitor that potently inhibits primary and resistant NTRK mutations

Oncogenic NTRK gene fusions occur at very low frequency in common cancers but high frequency in rare tumors including childhood malignances. The 1st-generation TRK inhibitors, e.g., larotectinib and entrectinib, have been used successfully to treat cancers carrying the NTRK fusions with excellent response rate and long duration. Nonetheless, duration of response may eventually be limited by acquired resistance mutations, such as TRKA-G595R or TRKC-G623R. We aimed at identifying a 2nd-generation inhibitor which can cover the primary TRK fusions and overcome the common resistant mutants induced by the 1st -generation TRK inhibitors. Using structural modeling to guide rational drug design, we discovered BPI-28592 as a 2nd-generation TRK inhibitor with desired potency and good drug-like properties. BPI-28592 is of a novel structure and possessed sub-nanomolar potency against a variety of primary TRK fusions. Importantly, the molecule exhibits low nanomolar inhibitory activity against acquired mutants commonly identified in patients who are refractory to 1st-generation TRK inhibitors, including TRKA-G595R TRKA-F589L, TRKA-G667C, and TRKC-G623R, etc. BPI-28592 showed a highly selective profile in a Kinome scan of 468 individual kinases. In cell-based assays, BPI-28592 dose-dependently inhibited proliferation of primary as well as resistant TRK mutant cell lines, blocked TRK protein phosphorylation and downstream signaling. Furthermore, BPI-29592 demonstrated in vivo efficacy in xenograft models derived from primary and resistant TRK mutant cells. BPI-28592 exhibited a profile of high oral exposure across multiple pre-clinical species, favorable ADME properties, and wide therapeutic window in pre-clinical toxicology studies. In conclusion, we discovered BPI-28592 as a novel, potent and selective next-generation TRK kinase inhibitor. The molecule has completed IND-enabling studies and is planned to enter Phase 1 clinical development in early 2020. Citation Format: Bang Fu, Dan Yan, Lingling Liu, Jing Guo, Jisheng Huang, Tianyi Ma, Yinlong Li, Wei Ren, Jie Chen, Xiangyong Liu, Hong Lan, Lieming Ding, Jiabing Wang. BPI-28592, a next-generation TRK kinase inhibitor that potently inhibits primary and resistant NTRK mutations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5315.