TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP-deleted cancers

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2025-02-01 DOI:10.1016/j.tranon.2024.102264

Kimberly J. Briggs, Kevin M. Cottrell, Matthew R. Tonini, Alice Tsai, Minjie Zhang, Douglas A. Whittington, Wenhai Zhang, Steven A. Lombardo, Satoshi Yoda, Erik W. Wilker, Samuel R. Meier, Yi Yu, Teng Teng, Alan Huang, John P. Maxwell

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引用次数: 0

Abstract

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).

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TNG908是一种脑渗透，mta协同PRMT5抑制剂，用于治疗mtap缺失的癌症。

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抑制和MTAP缺失之间的合成致死相互作用。MTAP缺失发生在代表多种组织学的所有人类癌症的10- 15%中。MTA是PRMT5的负调节因子，由于MTAP缺失而积累。在这项研究中，我们证明了TNG908选择性结合PRMT5·MTA复合物，在mtap缺失的癌症中驱动PRMT5的选择性抑制，这一机制相对于具有非肿瘤选择性的替代结合机制的第一代PRMT5抑制剂创造了一个大的治疗指数。在多种mtap缺失的异种移植物模型中具有很强的临床前活性，以及在临床前模型中显示的脑外显性，支持TNG908在mtap缺失的实体瘤（包括中枢神经系统恶性肿瘤）中具有组织学不可知的临床发展潜力。TNG908正在一项I/II期临床试验中对mtap缺失肿瘤（包括胶质母细胞瘤）患者进行临床测试（NCT05275478）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.