Briggs Kimberly J, Cottrell Kevin M, Tonini Matthew R, Tsai Alice, Zhang Minjie, Whittington Douglas A, Zhang Wenhai, Lombardo Steven A, Yoda Satoshi, Wilker Erik W, Meier Samuel R, Yu Yi, Teng Teng, Huang Alan, Maxwell John P
Tango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United States.
Tango Therapeutics, Tango Therapeutics, 201 Brookline Avenue, Boston, 02215, MA, United States.
Transl Oncol. 2025 Feb;52:102264. doi: 10.1016/j.tranon.2024.102264. Epub 2025 Jan 4.
TNG908 is a clinical stage PRMT5 inhibitor with an MTA-cooperative binding mechanism designed to leverage the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. MTAP deletion occurs in 10-15 % of all human cancer representing multiple histologies. MTA is a negative regulator of PRMT5 that accumulates as a result of MTAP deletion. In this study, we demonstrate that TNG908 selectively binds the PRMT5·MTA complex driving selective inhibition of PRMT5 in MTAP-null cancers, a mechanism that creates a large therapeutic index relative to first generation PRMT5 inhibitors that have alternative binding mechanisms that are not tumor-selective. Strong preclinical activity in multiple MTAP-deleted xenograft models, as well as demonstrated brain penetrance in preclinical models, support the potential for histology-agnostic clinical development of TNG908 in MTAP-deleted solid tumors, including CNS malignancies. TNG908 is being tested clinically in patients with MTAP-deleted tumors, including glioblastoma, in a Phase I/II clinical trial (NCT05275478).
TNG908是一种临床阶段的PRMT5抑制剂，具有MTA协同结合机制，旨在利用PRMT5抑制与MTAP缺失之间的合成致死相互作用。MTAP缺失发生在所有代表多种组织学类型的人类癌症的10%-15%中。MTA是PRMT5的负调节因子，由于MTAP缺失而积累。在本研究中，我们证明TNG908选择性结合PRMT5·MTA复合物，在MTAP缺失的癌症中驱动对PRMT5的选择性抑制，相对于具有非肿瘤选择性的替代结合机制的第一代PRMT5抑制剂，该机制产生了较大的治疗指数。在多个MTAP缺失的异种移植模型中的强大临床前活性，以及在临床前模型中显示的脑渗透性，支持了TNG908在包括中枢神经系统恶性肿瘤在内的MTAP缺失实体瘤中进行组织学无关临床开发的潜力。TNG908正在一项I/II期临床试验（NCT05275478）中对包括胶质母细胞瘤在内的MTAP缺失肿瘤患者进行临床测试。
