Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, No.19A Yuquan Road, 100049, Beijing, China.
Invest New Drugs. 2021 Oct;39(5):1213-1221. doi: 10.1007/s10637-021-01096-4. Epub 2021 Mar 12.
G-quadruplexes (G4s) are DNA or RNA structures formed by guanine-rich repeating sequences. Recently, G4s have become a highly attractive therapeutic target for BRCA-deficient cancers. Here, we show that a substituted quinolone amide compound, MTR-106, stabilizes DNA G-quadruplexes in vitro. MTR-106 displayed significant antiproliferative activity in homologous recombination repair (HR)-deficient and PARP inhibitor (PARPi)-resistant cancer cells. Moreover, MTR-106 increased DNA damage and promoted cell cycle arrest and apoptosis to inhibit cell growth. Importantly, its oral and i.v. administration significantly impaired tumor growth in BRCA-deficient xenograft mouse models. However, MTR-106 showed modest activity against talazoparib-resistant xenograft models. In rats, the drug rapidly distributes to tissues within 5 min, and its average concentrations were 12-fold higher in the tissues than in the plasma. Overall, we identified MTR-106 as a novel G-quadruplex stabilizer with high tissue distribution, and it may serve as a potential anticancer agent.
四链体（G4s）是由富含鸟嘌呤的重复序列形成的 DNA 或 RNA 结构。最近，G4s 已成为 BRCA 缺陷型癌症的一个极具吸引力的治疗靶点。在这里，我们展示了一种取代的喹诺酮酰胺化合物 MTR-106，它可以在体外稳定 DNA 四链体。MTR-106 在同源重组修复（HR）缺陷和 PARP 抑制剂（PARPi）耐药的癌细胞中表现出显著的抗增殖活性。此外，MTR-106 增加了 DNA 损伤，促进细胞周期停滞和细胞凋亡，从而抑制细胞生长。重要的是，它的口服和静脉给药显著抑制了 BRCA 缺陷的异种移植小鼠模型中的肿瘤生长。然而，MTR-106 对 talazoparib 耐药的异种移植模型的活性较弱。在大鼠中，药物在 5 分钟内迅速分布到组织中，其在组织中的平均浓度是血浆中的 12 倍。总的来说，我们鉴定出 MTR-106 是一种新型的具有高组织分布的四链体稳定剂，它可能成为一种有潜力的抗癌药物。
