PF-00477736

Our findings show that PF-477736 exerts anti-vascular remodeling effect by inhibiting phenotypic transition through the Chk1/p53/CD44 pathway in VSMCs, providing novel therapeutic strategies for preventing and treating vascular remodeling.

Synergistic cytolethal effects were achieved after combined treatment with low to moderate doses of the non-genotoxic RAD51-inhibitor (RAD51i) B02 and CHK1-inhibitor (CHK1i) PF477736. Based on these data, we suggest combined inhibition of RAD51 and CHK1 to overcome acquired cisplatin resistance of malignant cells. We propose that the molecular mechanism of this synergistic toxicity relies on a simultaneous inactivation of two key DNA damage tolerance pathways regulating replication fork restart, thereby circumventing the activation of alternative compensatory mechanisms and, in consequence, eventually effectively triggering apoptotic cell death by replication fork collapse.

Our data indicate that, rather than acting via abrogation of cell cycle checkpoints, ATR, CHK1 and WEE1 inhibitors cause an HRD phenotype and hence "induced synthetic lethality" with PARPi.

We have directly compared, for the first time, the cytotoxicity of four DDR inhibitors (rucaparib/PARPi, VE-821/ATRi, PF-477736/CHK1i and MK-1775/WEE1i) as single agents, and in combination with cisplatin and radiotherapy (RT) in a panel of CC cells. In mice, cisplatin-induced acute kidney injury was associated with oxidative stress and PARP activation and was prevented by rucaparib. Therefore, while all inhibitors investigated may increase the efficacy of CRT, the greatest clinical potential of rucaparib may be in limiting kidney damage, which is dose-limiting.