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.