PARP-1, a nuclear protein, is one of the key member of the DNA repair assembly and thereby emerged as an attractive target in anti-cancer drug discovery. PARP-1 plays a key role in terms of base excision repair, which is an important pathway for cell survival in breast cancer with BRCA1/BRCA2-mutation. In this scenario, the goal of this study was to identify novel prototypes of PARP-1 inhibitors for the development of antitumor therapeutics to treat breast cancer. Thus, a structure-based drug design exploration was first conducted using an in-house library, focusing on triazole-thione and alkylsulfanyl-triazole scaffold. Hits with good binding affinity and better predicted inhibitory potential were also tested for their PARP-1 inhibitory activity. Moreover, the selected compounds were evaluated for their cytotoxicity in-vitro. This approach led to the identification of few novel compounds showing interesting anti-proliferative potential in low micromolar range. Results disclosed that the identified lead molecules were efficiently impeding cell migration and cell proliferation, potentially by interfering with PARP-1 enzymatic activities.
Discovery of novel functionalized 1,2,4-triazoles as PARP-1 inhibitors in breast cancer: Design, synthesis and antitumor activity evaluation / Boraei, A. T. A.; Singh, Pankaj Kumar; Sechi, M.; Satta, Sandro. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 182:(2019), p. 111621. [10.1016/j.ejmech.2019.111621]
Discovery of novel functionalized 1,2,4-triazoles as PARP-1 inhibitors in breast cancer: Design, synthesis and antitumor activity evaluation
SINGH, Pankaj Kumar;Sechi M.;SATTA, Sandro
2019-01-01
Abstract
PARP-1, a nuclear protein, is one of the key member of the DNA repair assembly and thereby emerged as an attractive target in anti-cancer drug discovery. PARP-1 plays a key role in terms of base excision repair, which is an important pathway for cell survival in breast cancer with BRCA1/BRCA2-mutation. In this scenario, the goal of this study was to identify novel prototypes of PARP-1 inhibitors for the development of antitumor therapeutics to treat breast cancer. Thus, a structure-based drug design exploration was first conducted using an in-house library, focusing on triazole-thione and alkylsulfanyl-triazole scaffold. Hits with good binding affinity and better predicted inhibitory potential were also tested for their PARP-1 inhibitory activity. Moreover, the selected compounds were evaluated for their cytotoxicity in-vitro. This approach led to the identification of few novel compounds showing interesting anti-proliferative potential in low micromolar range. Results disclosed that the identified lead molecules were efficiently impeding cell migration and cell proliferation, potentially by interfering with PARP-1 enzymatic activities.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.