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
10.1016/j.apsb.2020.06.003
- Author:
Xiaosa CHANG
1
;
Dejuan SUN
1
;
Danfeng SHI
1
;
Guan WANG
1
;
Yanmei CHEN
1
;
Kai ZHANG
1
;
Huidan TAN
1
;
Jie LIU
1
;
Bo LIU
1
;
Liang OUYANG
1
Author Information
1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
- Publication Type:Journal Article
- Keywords:
BC, breast cancer;
BET, bromodomain and extra-terminal domain;
BRCA1/2, breast cancer susceptibility gene 1/2;
BRD4;
BRD4, bromodomain 4;
CDK4/6, cyclin-dependent kinase 4/6;
DSB, DNA double-strand break;
Dual-target inhibitor;
EGFR, epidermal growth factor receptor;
ELISA, enzyme linked immunosorbent assay;
ER, estrogen receptor;
ESI-HR-MS, high-resolution mass spectra;
FDA, U.S. Food and Drug Administration;
FITC, fluorescein isothiocyanate isomer I;
HE, hematoxylin-eosin;
HPLC, high-performance liquid chromatography;
HR, homologous recombination;
HRD, homologous recombination deficiency;
IHC, immunohistochemistry;
NHEJ, nonhomologous end-joining;
PARP1;
PARP1, poly(ADP-ribose) polymerase-1;
PI, propidium iodide;
PK, pharmacokinetics;
PPI, protein−protein interaction;
Quinazolin-4(3H)-one derivatives;
SAR, structure–activity relationship;
SOP, standard operation process;
Synthetic lethality;
TCGA, the cancer genome atlas;
TGI, tumor growth inhibition;
TLC, thin-layer chromatography;
TNBC, triple-negative breast cancer;
TR-FRET, time-resolved fluorescence resonance energy transfer.;
shRNA, short hairpin RNA
- From:
Acta Pharmaceutica Sinica B
2021;11(1):156-180
- CountryChina
- Language:English
-
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.
