Design, synthesis, and biological evaluation of quinoxalinone derivatives as potent BRD4 inhibitors.

The bromodomain-containing protein 4 (BRD4) has gained growing interest as an effective drug target for the treatment of hepatocellular carcinoma (HCC). Herein, we designed and synthesized a series of quinoxalinone derivatives as BRD4 inhibitors via scaffold hopping. The representative compound X9 showed potent BRD4 inhibitory activity (with IC50 = 82.3 nM), and preferable antiproliferative activity against HepG2 cells (with IC50 = 1.13 ± 0.07 µM), as well as less toxicity against GES-1 cells (with IC50 = 57.24 ± 5.46 µM). Furthermore, compound X9 dose-dependently inhibited colony formation and blocked the migration of HepG2 cells by down-regulating the expression of Snail and MMP-9 while up-regulating the E-cadherin and Occludin. Besides, compound X9 efficiently down-regulated the expression of c-Myc in HepG2 cells, induced apoptosis, and arrested at G0/G1 phase. In total, quinoxalinone was a potential core as BRD4 inhibitor and compound X9 might be effective for liver cancer therapy.

Discovery of novel VEGFR-2-PROTAC degraders based on the localization of lysine residues via recruiting VHL for the treatment of gastric cancer.

VEGFR-2 is an attractive therapeutic target for antitumor drug research by blocking tumor angiogenesis and PROTAC provides a new technology for targeted protein knockout. Herein, a library of novel VEGFR-2-PROTAC degraders were rationally designed and synthesized based on the Lys residue region on the surface of VEGFR-2 protein using protein structure-based drug design strategy. Among them, P7 exhibited preferable antitumor activity against HGC-27 cells and less toxic to human normal HUVEC, HEK293T and GES-1 cells in vitro, as well as the potent degradation activity of VEGFR-2 protein in HGC-27 cells (DC50: 0.084 ± 0.04 µM, Dmax: 73.7%) and HUVEC cells (DC50: 0.51 ± 0.10 µM, Dmax: 76.6%). Additionally, P7 degraded VEGFR-2 protein by the formation of ternary complex and the ubiquitin proteasome pathway in HGC-27 cells. Furthermore, P7 shortened the half-life of VEGFR-2 protein synthesis and had no inhibitory effect on the expression of VEGFR-2 mRNA in HGC-27 cells. Moreover, P7 inhibited the colony formation, migration and invasion of HGC-27 cells in a time- and dose-dependent manner, and meanwhile induced G2/M phase cycle arrest and apoptosis. All the results demonstrated that P7 could be as a promising VEGFR-2-PROTAC degrader for gastric cancer therapy.

Design, synthesis and biological evaluation of coumarin derivatives as potential BRD4 inhibitors.

The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer. Coumarin is a highly privileged moiety for the development of novel anticancer drugs which has been identified in clinical trials for the treatment of various cancers. Herein, we modified BRD4i ABBV-075 with a coumarin ring and synthesized a novel series of coumarin derivatives as BRD4 inhibitors. Among them, the representative compound 27d showed excellent BRD4 inhibitory activities with an IC50 value of 99 nM in the TR-FRET assay. Compared with ABBV-075, compound 27d displayed a favorable cell proliferation inhibitory activity in solid tumors, such as MCF-7, HGC-27 and HepG-2. Further mechanism investigation illustrated that 27d-treatment resulted in G0/G1 phase arrest and promoted apoptosis of MCF-7 cells. Compound 27d also blocked colony formation in a concentration-dependent manner in McF-7 cell lines. As the downstream-protein of BRD4, the expression of c-Myc was decreased in a dose-dependent manner after the treatment of compound 27d. Moreover, compound 27d also exhibited good in vivo and in vitro metabolic stability. All the findings meaningfully make it as a promising lead compound for further drug development.