olaparib and Breast-Neoplasms

Topics: Anti-Bacterial Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; MCF-7 Cells; Quinolines; Receptor, Bradykinin B2

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.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; MCF-7 Cells; Models, Molecular; Molecular Structure; Poly (ADP-Ribose) Polymerase-1; Structure-Activity Relationship; Triazoles; Wound Healing

7-Azaindole-1-carboxamides were designed as a new class of PARP-1 inhibitors. The compounds displayed a variable pattern of target inhibition profile that, in part, paralleled the antiproliferative activity in cell lines characterized by homologous recombination defects. A selected compound (1l; ST7710AA1) showed significant in vitro target inhibition and capability to substantially bypass the multidrug resistance mediated by Pgp. In antitumor activity studies against the MX1 human breast carcinoma growth in nude mice, the compound exhibited an effect similar to that of Olaparib in terms of tumor volume inhibition when used at a lower dose than the reference compound. Treatment was well tolerated, as no deaths or significant weight losses were observed among the treated animals.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; HeLa Cells; Homologous Recombination; Humans; Indoles; Mice; Mice, Nude; Models, Molecular; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays