MRTX1719是一种MTA合作的PRMT5抑制剂，在临床前模型和MTAP缺失癌症患者中显示出合成致死效应。
MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP deleted cancer.
发表日期：2023 Aug 08
作者：
Lars D Engstrom, Ruth Aranda, Laura Waters, Krystal Moya, Vickie Bowcut, Laura Vegar, David Trinh, Allan Hebbert, Christopher R Smith, Svitlana Kulyk, J David Lawson, Leo He, Laura D Hover, Julio Fernandez-Banet, Jill Hallin, Darin Vanderpool, David M Briere, Alice Blaj, Matthew A Marx, Jordi Rodon, Michael Offin, Kathryn C Arbour, Melissa L Johnson, David J Kwiatkowski, Pasi A Janne, Candace L Haddox, Kyriakos P Papadopoulos, Jason T Henry, Konstantinos Leventakos, James G Christensen, Ronald Shazer, Peter Olson
来源：
Cancer Discovery
摘要：
先前的研究表明PRMT5是MTAP删除（MTAP del）癌症的合成致死靶点，然而，还没有描述能够重新呈现合成致死表型的小分子抑制剂的药理学特征。MRTX1719在MTAP del癌症中，选择性地抑制了存在MTA的PRMT5，并与HCT116 MTAP del细胞相比抑制了PRMT5依赖活性和细胞存活，选择性增加了超过70倍。MRTX1719呈剂量依赖的抗肿瘤活性和抑制MTAP del肿瘤中PRMT5依赖的SDMA修饰。相比之下，MRTX1719对MTAP WT肿瘤异种移植、小鼠或人类造血细胞的SDMA和细胞存活影响很小。MRTX1719在一系列异种移植模型中以耐受剂量展现出明显的抗肿瘤活性。在1/2期的研究中观察到早期的临床活性迹象，包括MTAP del黑色素瘤、胆囊腺癌、间皮瘤、非小细胞肺癌以及MPNST患者中的客观反应。
Previous studies implicated PRMT5 as a synthetic lethal target for MTAP deleted (MTAP del) cancers, however, the pharmacological characterization of small molecule inhibitors that recapitulate the synthetic lethal phenotype have not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selectivity in HCT116 MTAP del compared to HCT116 MTAP WT cells. MRTX1719 demonstrated dose-dependent anti-tumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts, mouse or human hematopoietic cells. MRTX1719 demonstrated marked anti-tumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and MPNST from the Phase 1/2 study.