Synthesis of novel dual target inhibitors of PARP and EGFR and their antitumor activities in triple negative breast cancers

The therapeutic strategy of poly (ADP-ribose) polymerase (PARP) inhibition of BRCA1/2 mutant cancers has been overwhelmingly successful, however, the highly aggressive triple negative breast cancers (TNBC) that receptor protein tyrosine kinase (RTKs) is known to be overexpressed are not sensitive to PARP inhibitors. Our research focused on exploring PARP inhibitors incorporating a bicyclic tetrahydropyridine pyrimidine. All synthesized compounds were more potent than Olaparib (ola) in killing tumor cells, especially in TNBC. Furthermore, compound 7 exhibited strong inhibitory effects on PARP enzymatic activity, moreover, the expression of EGFR and phosphorylated EGFR was inhibited by compound 7. Therefore, compound 7 can effectively inhibit TNBC cells with high expression of EGFR. In addition, significant synergistic effect of antitumor effect of new PARP inhibitors and adriamycin was also observed.

Automated summary

This research focused on exploring new PARP inhibitors that are more potent in killing triple negative breast cancer cells and effectively inhibit the overexpression of receptor protein tyrosine kinase.