3/2/2023 0 Comments Flashfrozen emberIntense efforts are underway to develop chemically diverse and highly potent BRD4 inhibitors as new cancer therapeutics ( 6). Importantly, BRD4 inhibition downregulates oncogenic MYC transcription factors in several cancer cell lines. All known BRD4 inhibitors target the KAc recognition site, particularly through H-bonding interactions with a conserved Asn residue. Chemical inhibition of BRD4 exerts a broad spectrum of desirable biologic effects such as anticancer and anti-inflammatory properties ( 5). BRD4 is overexpressed in various cancers and can undergo translocations that are a hallmark of the lethal tumor NUT midline carcinoma ( 4). The BET protein BRD4 facilitates transcriptional elongation via recruitment of the positive transcription elongation factor (P-TEFb) and displacement of negative regulators such as HEXIM1 and 7SK snRNA ( 3). Members of the bromodomain and extra terminal (BET) protein family (BRD2, BRD3, BRD4, and BRDT) have been implicated in a number of disease pathways and are therefore considered promising drug targets ( 2). BRDs regulate transcription, chromatin remodeling, gene splicing, protein scaffolding and signal transduction and, therefore, play fundamental roles in cell proliferation and division. ©2017 AACR.īromodomains (BRD) are about 110 amino acid domains that bind to and “read” acetylated lysine (KAc) residues of histones tails in a process critical for chromatin organization and gene transcription ( 1). Combined, our findings indicate promising potential of these agents as novel chemical probes and cancer therapeutics. Gene drug sensitivity analyses and drug combination studies indicate synergism of BRD4 and kinase inhibition as a plausible reason for the superior potency in cell killing. Screening across 931 cancer cell lines revealed differential growth inhibitory potential with highest activity against bone and blood cancers and greatly enhanced activity over the single BET inhibitor JQ1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from patients with myeloproliferative neoplasm. Using the chemical scaffold of the JAK2 inhibitor TG101348, we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |