Discovery, Synthesis, and Evaluation of Novel Dual Inhibitors of a Vascular Endothelial Growth Factor Receptor and Poly(ADP-Ribose) Polymerase for BRCA Wild-Type Breast Cancer Therapy

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 14b is identified to exert promising activities against VEGFR and PARP
in the nanomolar range and possesses significant in vitro and in vivo antitumor and antimetastasis features.
It also presented a favorable pharmacokinetic characteristics in rats
with an oral bioavailability of 60.1%. Collectively, 14b may be a promising therapeutic agent of BRCA wild-type BC.

聚腺苷二磷酸核糖聚合酶（Poly(ADP-ribose) polymerase, PARP）抑制剂已获批用于治疗携带乳腺癌易感基因（breast cancer susceptibility gene, BRCA）突变的乳腺癌（breast cancer, BC）患者。发掘新型合成致死相互作用，或是拓宽PARP抑制剂对BRCA野生型乳腺癌患者适应症的有效策略。据报道，血管内皮生长因子受体（vascular endothelial growth factor receptor, VEGFR）介导的血管生成（angiogenesis）抑制作用，可通过合成致死效应提升BRCA野生型肿瘤细胞对PARP抑制剂的敏感性。本研究将PARP抑制剂与VEGFR抑制剂药效团（pharmacophore）进行缀合，构建得到兼具VEGFR和PARP双重抑制活性的化合物。经筛选得到的活性最优化合物14b，可在纳摩尔级别下对VEGFR与PARP展现出优异的抑制活性，同时具备显著的体外（in vitro）与体内（in vivo）抗肿瘤及抗转移特性。该化合物在大鼠体内亦展现出良好的药代动力学特性（pharmacokinetic characteristics），口服生物利用度达60.1%。综上，化合物14b有望成为治疗BRCA野生型乳腺癌的潜在候选治疗药物。