在多种功能基因组筛选中观察到的最强大的合成致死相互作用之一是 MTAP 缺失的癌细胞对 PRMT5 的依赖。我们报告了临床阶段 MTA 协同 PRMT5 抑制剂 AMG 193 的发现，它在 MTA 存在的情况下优先结合 PRMT5，并且在跨多个癌症谱系的 MTAP 缺失细胞中具有有效的生化和细胞活性。在体外，PRMT5 抑制会在 MTAP 缺失的细胞中诱导 DNA 损伤、细胞周期停滞和异常的选择性 mRNA 剪接。在人类细胞系和患者来源的异种移植模型中，AMG 193 诱导强大的抗肿瘤活性，并且耐受性良好，对正常造血细胞谱系没有影响。 AMG 193 在体外与化疗或 KRAS G12C 抑制剂 sotorasib 协同作用，在体内联合治疗可显着抑制肿瘤生长。 AMG 193 正在展现出有前景的临床活性，包括一项正在进行的 1/2 期研究证实对 MTAP 缺失的实体瘤患者有部分缓解。

One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.