MRTX-1719

MRTX-1719 is a potent, selective inhibitor of the PRMT5, with an average IC₅₀ 20.4nM without MTA and 3.6nM with MTA present. PRMT5 (protein arginine methyltransferase 5) is an enzyme that catalyzes symmetric demethylation of arginine residues on target proteins, regulating essential cellular functions such as RNA splicing, transcription, and translation. MTAP (methylthioadenosine phosphorylase) loss was commonly found in cancer, which can lead to MTA accumulation. Elevated MTA (5'-deoxy-5'-methylthioadenosine) acts as a competitive inhibitor of PRMT5, partially inhibiting its activity. In cancer, PRMT5 is particularly important because its activity becomes a synthetic lethal vulnerability in tumors with MTAP deletion, making it a promising therapeutic target^[1]. MRTX-1719 selectively binds to the PRMT5-MTA complex, retaining PRMT5 in a catalytically inactive state, further inhibiting its methyltransferase activity and exploiting the synthetic lethal vulnerability of MTAP-deleted tumors. MRTX-1719 is a potent, orally bioavailable small-molecule inhibitor with K_D of 0.14pM for the MTA/PRMT5 complex and 9.4pM for SAM-bound PRMT5, high selectivity for the PRMT5-MTA complex, long dissociation half-life (∼14 days), and demonstrates strong selectivity and antitumor activity in MTAP-deleted cancer models^[2].

In vitro, treatment of isogenic MTAP-del and WT HCT116 cells with MRTX-1719 (0-10μM) for 4 days significantly inhibited PRMT5-dependent SDMA levels with IC₅₀ values of 8nM for MTA-del cells and 653nM for WT cells. Treatment of isogenic MTAP-del and WT HCT116 cells with MRTX-1719(0-10μM) for 10 days significantly reduced cell viability with IC₅₀ values of 12nM for MTA-del cells and 890nM for WT cells. Overall selectivity of MRTX-1719 reach to 82-fold in SDMA assay and 74 -fold in viability assay. Treatment of isogenic MTAP-del and WT PK-1 cells with MRTX-1719 (0-10μM) for 10 days significantly reduced cell viability with IC₅₀ values of 7.1nM for MTA-del cells and 818nM for WT cells^[3].

In human tumor xenograft animal models, oral administration of MRTX-1719 (50 or 100mg/kg/day) for 22 days remarkably reduce the growth of colorectal cancer cells in mice bearing HCT116 cell xenografts showed specificity to MTAP-del tumor xenografts. In patient-derived xenograft (PDX) animal models, oral administration of MRTX-1719 (100mg/kg/day) for 60 days significantly reduce the growth of colorectal cancer cells in mice with 99% TGI (Tumor Growth Inhibition value) at 50 days^[3]. Oral administration of MRTX-1719 (30mg/kg/day) for 7 days can efficiently decreased SDMA levels in mice and inhibit PRMT5 function in MTAP-loss tumors. Combination therapy of MRTX-1719 and anti‑PD‑1 antibody significantly reduced tumor volume and enhancing tumor sensitivity to immune attacks ^[4].

References:
[1] Mavrakis, Konstantinos J., et al. "Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5." Science 351.6278 (2016): 1208-1213.
[2] Smith, Christopher R., et al. "Fragment-based discovery of MRTX1719, a synthetic lethal inhibitor of the PRMT5• MTA complex for the treatment of MTAP-deleted cancers." Journal of Medicinal Chemistry 65.3 (2022): 1749-1766.
[3] Engstrom, Lars D., et al. "MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP-deleted cancer." Cancer discovery 13.11 (2023): 2412-2431.
[4] Chen, Si, et al. "MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors." Journal for immunotherapy of cancer 12.9 (2024): e009600.

MRTX-1719 是一种强效、选择性的 PRMT5 抑制剂，未添加 MTA 时的平均 IC₅₀ 为 20.4nM，添加 MTA 后为 3.6nM。PRMT5（蛋白质精氨酸甲基转移酶 5）是一种催化靶蛋白上精氨酸残基去甲基化的酶，调控 RNA 剪接、转录和翻译等基本细胞功能。在癌症中，MTAP（甲硫腺苷磷酸化酶） 基因的缺失常被发现，MTAP 的缺失会导致 MTA（Methylthioadenosine） 的积累。MTA 的积累会选择性地与细胞中 PRMT5 结合，抑制 PRMT5 在细胞中的正常生理功能。PRMT5 尤为重要，因为其活性在 MTAP 缺失的肿瘤中合成致死，使其成为一个有前景的治疗靶点^[1]。MRTX-1719 选择性地与 PRMT5-MTA 复合物结合，将 PRMT5 保持在失活状态，进一步抑制其甲基转移酶活性。MRTX-1719 是一种强效的口服生物可利用的小分子抑制剂，其与MTA/PRMT5 复合物相结合的解离常数 (K_D) 为 0.14pM，与SAM/PRMT5 复合物相结合的 K_D 为9.4pM。MRTX-1719对 PRMT5-MTA 复合物具有高度选择性以及较长的解离半衰期（约 14 天），并在 MTAP 缺失的癌症模型中表现出强选择性和抗肿瘤活性^[2]。

在体外实验中，使用 MRTX-1719（0-10μM）处理 MTAP 缺失和 WT HCT116 细胞 4 天后，MRTX-1719显著抑制了 PRMT5 依赖的 SDMA 水平，MTAP 缺失细胞中其 IC₅₀ 值为 8nM，而 WT 细胞中其 IC₅₀为 653nM。使用 MRTX-1719（0-10μM）处理 MTAP 缺失和 WT HCT116 细胞 10 天也显著降低了细胞活性，在MTAP 缺失细胞的细胞中其 IC₅₀ 值为 12nM，而 在WT 细胞中则为 890nM。MRTX-1719 在 SDMA 测定中的选择性为 82 倍，在细胞活性测定中的选择性为 74 倍。使用 MRTX-1719（0-10μM）处理 MTAP 缺失和 WT PK-1 细胞 10 天后，MRTX-1719也显著降低了其细胞活性，在MTAP 缺失细胞中其 IC₅₀ 值为 7.1nM，而 在WT 细胞中为 818nM^[3]。

在人体肿瘤异种移植动物模型中，口服 MRTX-1719（50 或 100 mg/kg/天）22 天显著抑制了携带 HCT116 细胞异种移植的鼠类结直肠癌细胞的生长，并显示出MRTX-1719对 MTAP 缺失肿瘤异种移植的特异性。在患者衍生异种肿瘤移植（PDX）动物模型中，口服 MRTX-1719（100mg/kg/天）60 天也显著减少了结直肠癌细胞在小鼠中的生长，50 天时的肿瘤抑制率（TGI）达到 99%。口服 MRTX-1719（30mg/kg/天）7 天能有效降低小鼠部分器官中 SDMA 水平，抑制 MTAP 缺失肿瘤中的 PRMT5 功能。MRTX-1719 与抗 PD-1 抗体的联合治疗可以显著减少肿瘤体积，并增强了肿瘤对免疫攻击的敏感性^[4]。