2. Academic Validation
  3. Synthesis of novel dual target inhibitors of PARP and EGFR and their antitumor activities in triple negative breast cancers

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

  • Bioorg Med Chem. 2022 May 1:61:116739. doi: 10.1016/j.bmc.2022.116739.
Shanshan Lin 1,  Xiao Zhang 2,  Zelei Yu 1,  Xiuwang Huang 3,  Jianhua Xu 1,  Yang Liu 4,  Lixian Wu 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, P.R. China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, P. R. China.
  • 2 Yuncheng Central Hospital, Yuncheng, P.R. China.
  • 3 Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, P. R. China; Department of Public Technology Service Center, Fujian Medical University (FMU), Fuzhou, P.R. China.
  • 4 Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, P. R. China; Department of Pharmacochemistry, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, P.R. China. Electronic address: liuyang966@163.com.
  • 5 Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, P.R. China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, P. R. China. Electronic address: wlx-lisa@126.com.
PMID: 35393219 DOI: 10.1016/j.bmc.2022.116739
Abstract

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 anti-tumor effect of new PARP inhibitors and adriamycin was also observed.

Keywords

Antitumor; EGFR; PARP inhibitor; TNBC; Tetrahydropyrido[4,3d] pyrimidines.

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