Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

Abstract

This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 ( BRCA1/2 ) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.

Structural insights into targeting of the colchicine binding site by ELR510444 and parbendazole to achieve rational drug design

“…Here, the cyano group could be extended to interact with Asn165. Since computer-aided drug design plays an important role in drug discovery, 27 we also conducted molecular docking experiments on this tubulin complex. A series of ELR510444 derivatives with different substituents was designed and docked into the CBS by Autodock Vina.…”

Circulating Tumor Cells in Breast Cancer Patients: A Balancing Act between Stemness, EMT Features and DNA Damage Responses

“…In particular, inhibitors of PARP1 together with the DNA damage response kinases ATR, CHK1 or WEE1 are being investigated in clinical trials [ 225 ]. Dual inhibitory molecules, co-targeting PARP1 and Bromodomain 4 (BRD4), which executes key functions in multiple processes including DNA damage responses, or PARP1 and RAD51, the key recombinase in HR, have been found to sensitize MBC cell lines regardless of hormone receptor status, BRCAness, or acquired resistance [ 226 , 227 ]. Suggesting the validity of these concepts for the eradication of CTCs, Gong and colleagues [ 149 ] demonstrated that chemoresistance due to the enhanced DNA repair in CTCs versus primary BC can be broken by adding inhibitors of the DNA damage response kinases CHK1 or CHK2.…”

Design, synthesis and pharmacological characterization of N-(3-ethylbenzo[d]isoxazol-5-yl) sulfonamide derivatives as BRD4 inhibitors against acute myeloid leukemia

“…Therefore, the expression of key oncogenes can be inhibited through the displacement of BRD4 from chromatin. Accumulative evidence indicates that BRD4 protein has been implicated in various human diseases, including acute myeloid leukemia (AML) [ 8 – 10 ], prostate cancer [ 11 , 12 ], breast cancer [ 13 – 15 ], gastrointestinal stromal tumor (GIST) [ 16 ], neuroblastoma [ 17 ], pancreatic cancer [ 18 , 19 ], cholangiocarcinoma [ 20 ] as well as inflammations [ 21 , 22 ].…”