Discovery of novel PARP/PI3K dual inhibitors with high efficiency against BRCA-proficient triple negative breast cancer.

Co-targeting PARP and PI3K by PARP/PI3K dual inhibitors has been recognized as a promising chemotherapeutic strategy for the treatment of triple negative breast cancer (TNBC) in our previous work. To further explore novel and more potent PARP/PI3K dual inhibitors, a series of compounds were designed, synthesized and evaluated for their pharmacological properties, resulting in the candidate compound 12, a potent and highly selective PARP/PI3K dual inhibitor. Compared to Olaparib, compound 12 exhibits a superior antiproliferative profile against BRCA-proficient MDA-MB-468 cells. In MDA-MB-468 cell-derived xenograft model, compound 12 displayed excellent antitumor efficacy at a dose of 50 mg/kg, which is considerably more efficacious than the single administration of Olaparib or BKM120. Furthermore, compound 12 displayed good metabolic stability and high safety. Taken together, these results suggest that compound 12 as a novel PARP/PI3K dual inhibitor is worthy for further study.

Wang J ，He G ，Li H ，Ge Y ，Wang S ，Xu Y ，Zhu Q ... -  《-》

BKM120 sensitizes BRCA-proficient triple negative breast cancer cells to olaparib through regulating FOXM1 and Exo1 expression.

Li Y ，Wang Y ，Zhang W ，Wang X ，Chen L ，Wang S ... -  《Scientific Reports》

Discovery of dual-targeted molecules based on Olaparib and Rigosertib for triple-negative breast cancer with wild-type BRCA.

PARP inhibitors (PARPis) demonstrate significant potential efficacy in the clinical treatment of BRCA-mutated triple-negative breast cancer (TNBC). However, a majority of patients with TNBC do not possess BRCA mutations, and therefore cannot benefit from PARPis. Previous studies on multi-targeted molecules derived from PARPis or disruptors of RAF-RAF pathway have offered an alternative approach to develop novel anti-TNBC agents. Hence, to broaden the application of PARP inhibitors for TNBC patients with wild-type BRCA, a series of dual-targeted molecules were constructed via integrating the key pharmacophores of Olaparib (Ola) and Rigosertib into a single entity. Subsequent studies exhibited that the resulting compounds 13a-14c obtained potential anti-proliferative activity against BRCA-defected or wild-type TNBC cells. Among them, an optimal compound 13b showed good inhibitory activity toward PARP-1, displayed approximately 34-fold higher inhibitory activity than that of Ola in MDA-MB-231 cells, and exerted multi-functional mechanisms to induce apoptosis. Moreover, 13b displayed superior antitumor efficacy (TGI, 61.3 %) than the single administration of Ola (TGI, 38.5 %), 11b (TGI, 51.8 %) or even their combined administration (TGI, 56.7 %), but did not show significant systematic toxicity. These findings suggest that 13b may serve as a potential candidate for BRCA wild-type TNBC.

Liu Z ，Mao S ，Dai L ，Huang R ，Hu W ，Yu C ，Yang Y ，Cao G ，Huang X ... -  《-》

Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy.

Wang J ，Li H ，He G ，Chu Z ，Peng K ，Ge Y ，Zhu Q ，Xu Y ... -  《-》

Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes.

Combined inhibition of PI3K and PARP has been shown to be effective in the treatment of preclinical models of breast cancer and prostate cancer independent of BRCA or PIK3CA mutational status. However, the knowledge about this combination treatment in ovarian cancer is limited. The aim of this study was to evaluate the therapeutic effect of PI3K inhibitor BKM120 and PARP inhibitor Olaparib on ovarian cancer cell lines bearing wild-type PIK3CA genes. We exposed three wild-type PIK3CA ovarian cancer cell lines to a PI3K inhibitor BKM120 and/or a PARP inhibitor Olaparib. The effect of BKM120 as a single-agent or in combination with Olaparib was evaluated by Cell Count Kit (CCK8) assay, immunoblotting, comet assay, flow cytometry and immunofluorescence staining assay. The combination indexes for synergistic effect on cell viability were calculated with the Chou-Talalay method. Ex vivo cultured ovarian cancer tissues from patients were analyzed by histological and immunohistochemical analyses. Combined inhibition of PI3K and PARP effectively synergized to block the growth of three wild-type PIK3CA ovarian cancer cell lines and explants of a primary ovarian tumor specimen. Mechanistically, dual blockade of PI3K and PARP in these ovarian cancer cell lines resulted in substantially attenuated PI3K/AKT/mTOR signaling, impaired DNA damage response and deficient homologous recombination repair, with remarkable BRCA downregulation. The combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib may be effective in ovarian cancers with a broader spectrum of cancer-associated genetic alterations but not limited to those with mutant PIK3CA or BRCA genes. BRCA downregulation may be a potential biomarker for the effective response to the proposed combination treatment.

Wang D ，Li C ，Zhang Y ，Wang M ，Jiang N ，Xiang L ，Li T ，Roberts TM ，Zhao JJ ，Cheng H ，Liu P ... -  《-》