Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China.
Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China.
J Med Chem. 2023 Sep 14;66(17):12069-12100. doi: 10.1021/acs.jmedchem.3c00640. Epub 2023 Aug 24.
Poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for the treatment of breast cancer (BC) with breast cancer susceptibility (BRCA) gene mutation. Leveraging new synthetic lethal interactions may be an effective way to broaden the indication of PARP inhibitors for BC patients with wild-type BRCA. Vascular endothelial growth factor receptor (VEGFR)-mediated suppression of angiogenesis has been reported to improve the sensitivity of wild-type BRCA cells to PARP inhibitors through synthetic lethality. Herein, we reported the conjugation of a PARP inhibitor with a VEGFR inhibitor pharmacophore to construct dual VEGFR and PARP inhibitors. The most potent compound is identified to exert promising activities against VEGFR and PARP in the nanomolar range and possesses significant and antitumor and antimetastasis features. It also presented a favorable pharmacokinetic characteristics in rats with an oral bioavailability of 60.1%. Collectively, may be a promising therapeutic agent of BRCA wild-type BC.
聚（ADP-核糖）聚合酶（PARP）抑制剂已被批准用于治疗携带有乳腺癌易感基因（BRCA）突变的乳腺癌（BC）。利用新的合成致死相互作用可能是拓宽 PARP 抑制剂用于 BRCA 野生型 BC 患者适应证的有效方法。血管内皮生长因子受体（VEGFR）介导的血管生成抑制已被报道通过合成致死作用提高野生型 BRCA 细胞对 PARP 抑制剂的敏感性。在此，我们报道了将 PARP 抑制剂与 VEGFR 抑制剂药效团连接起来构建双重 VEGFR 和 PARP 抑制剂。最有效的化合物被鉴定为在纳摩尔范围内对 VEGFR 和 PARP 具有有前景的活性，并具有显著的抗肿瘤和抗转移特征。它在大鼠中也表现出良好的药代动力学特征，口服生物利用度为 60.1%。总之，可能是一种有前途的 BRCA 野生型 BC 的治疗剂。
