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

Abstract

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 wildtype BC.

Rational Design of PARP1/c-Met Dual Inhibitors for Overcoming PARP1 Inhibitor Resistance Induced by c-Met Overexpression

“…To date, four dual-target design strategies have been documented, namely, the merged-pharmacophore mode, fused-pharmacophore mode, noncleavable pharmacophore linking mode, and cleavable pharmacophore linking mode. The noncleavable pharmacophore linking strategy based on pharmacophore targeting two different targets through a series of linkers is wildly utilized and effective in obtaining dual-target inhibitors with a synergistic mechanism. − The noncleavable pharmacophore linking strategy can enhance the biological activity of small molecules through synergistic interactions between two targets. However, the resulting compounds obtained from this approach often exhibit high relative molecular weight and poor drug-like properties, which presents a significant challenge for designing dual-target compounds.…”