jq1-compound and Neoplasms

Histone deacetylases (HDACs) play an important role in regulating target gene expression. They have been highlighted as a novel category of anticancer targets, and their inhibition can induce apoptosis, differentiation, and growth arrest in cancer cells. In view of the fact that HDAC inhibitors and other antitumor agents, such as BET inhibitors, topoisomerase inhibitors, and RTK pathway inhibitors, exert a synergistic effect on cellular processes in cancer cells, the combined inhibition of two targets is regarded as a rational strategy to improve the effectiveness of these single-target drugs for cancer treatment. In this review, we discuss the theoretical basis for designing HDAC-involved dual-target drugs and provide insight into the structure-activity relationships of these dual-target agents.

Topics: Antineoplastic Agents; DNA Damage; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Neoplasms; Protein Kinases; Proteins; Structure-Activity Relationship; Topoisomerase Inhibitors

EZH2 inhibitors that prevent trimethylation of histone lysine 27 (H3K27) are often limited to the treatment of a subset of hematological malignancies. In most solid tumors, EZH2 inhibitors induce reciprocal H3K27 acetylation that subsequently results in acquired drug resistance. The combination of EZH2 and BRD4 inhibitors to resensitize solid cancer cells to EZH2 inhibitors has proven to be effective, underlying the significance of developing dual inhibitors. Herein, we present the design, synthesis, and biological evaluation of first-in-class dual EZH2/BRD4 inhibitors. Our most promising compound, YM458, displays potent inhibitory activity against EZH2 and BRD4 and remarkable antiproliferative capacity against 11 solid cancer cell lines. Its in vivo therapeutic potential is validated in both lung cancer and pancreatic cancer xenograft tumor mice models, highlighting the potential of EZH2/BRD4 dual inhibitors to target a broad scope of EZH2 inhibitor-resistant solid tumors.

Topics: Animals; Cell Cycle Proteins; Cell Line, Tumor; Enhancer of Zeste Homolog 2 Protein; Histones; Humans; Mice; Neoplasms; Nuclear Proteins; Transcription Factors

BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound

Topics: Animals; Antineoplastic Agents; Cell Cycle Proteins; Cell Proliferation; Crystallography, X-Ray; Drug Design; Drug Discovery; Humans; Inhibitory Concentration 50; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, Nude; Mice, SCID; Microsomes, Liver; Molecular Structure; Neoplasm Transplantation; Neoplasms; Nuclear Proteins; Peptides; Protein Domains; Proteins; Transcription Factors