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Dual target PARP1/EZH2 inhibitors inducing excessive autophagy and producing synthetic lethality for triple-negative breast cancer therapy.
- Source :
-
European Journal of Medicinal Chemistry . Feb2024, Vol. 265, pN.PAG-N.PAG. 1p. - Publication Year :
- 2024
-
Abstract
- Currently available PARP inhibitors are mainly used for the treatment of BRCA-mutated triple-negative breast cancer (TNBC), with a narrow application range of approximately 15% of patients. Recent studies have shown that EZH2 inhibitors have an obvious effect on breast cancer xenograft models and can promote the sensitivity of ovarian cancer cells to PARP inhibitors. Here, a series of new dual-target PARP1/EZH2 inhibitors for wild-BRCA type TNBC were designed and synthesized. SAR studies helped us identify compound 12e , encoded KWLX-12e , with good inhibitory activity against PARP1 (IC 50 = 6.89 nM) and EZH2 (IC 50 = 27.34 nM). Meanwhile, KWLX-12e showed an optimal cytotoxicity against MDA-MB-231 cells (IC 50 = 2.84 μM) and BT-549 cells (IC 50 = 0.91 μM), with no toxicity on normal breast cell lines. KWLX-12e also exhibited good antitumor activity with the TGI value of 75.94%, more effective than Niraparib plus GSK126 (TGI = 57.24%). Mechanistic studies showed that KWLX-12e achieved synthetic lethality indirectly by inhibiting EZH2 to increase the sensitivity to PARP1, and induced cell death by regulating excessive autophagy. KWLX-12e is expected to be a potential candidate for the treatment of TNBC. [Display omitted] • Novel dual-target PARP1/EZH2 inhibitors were designed and synthesized. • KWLX-12e showed potential inhibitory activity on PARP1/EZH2 and had no toxicity. • KWLX-12e increased sensitivity to PARP1 by inhibiting EZH2. • KWLX-12e could significantly inhibit tumor growth and proliferation. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 265
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 174789263
- Full Text :
- https://doi.org/10.1016/j.ejmech.2023.116054