Recently, we reported the development and biochemical characterization of a potent, selective smallmolecule inhibitor of bet bromodomains, jq1 figure 1a filippakopoulos et al. B transcriptional activity in hivassociated kidney disease by brd4 inhibition. Bet bromodomain inhibition as a novel strategy for. So far, successful efforts have been limited to chromatin modifying enzymes, or socalled epigenetic writers and erasers. Bromdomains are the readers of acetylated histone marks, and, consequently, bromodomaincontaining proteins have a variety of chromatinrelated functions. The role of bromodomains in translating a deregulated cell acetylome into disease phenotypes was recently unveiled by the development of small molecule bromodomain inhibitors.
The study was designed with two independent and parallel cohorts, one in patients with acute leukaemia and the other in patients with nonleukaemic haematological malignancies. In spite of the structural similarity to rvx208, rvx297 has demonstrated a different pharmacodynamical profile, as well as distinct cellular and biological activity which was elucidated in the autoimmune disease models of multiple sclerosis and. Bromodomaincontaining proteins are of substantial biological. Pf1 is a potent and highly selective dihydroquinazoline2one inhibitor, which blocks the interaction of bet bromodomains with acetylated histone tails. The effect of this inhibitor is far more selective than that observed for the pan bet bromodomain inhibitor jq1. A small set of superenhancers associated with oncogenes such as myc was cooccupied by brd4 and mediator in multiple myeloma. Bromodomains are small nuclear proteins that selectively bind to acetylated lysine residues of histone proteins1. Discovery and characterization of small molecule inhibitors. Discovery of i brd9, a selective cell active chemical. With that aim, we examined whether bet bromodomain inhibition had any functional impact on the. Request pdf selective inhibition of the bd2 bromodomain of bet proteins in prostate cancer proteins of the bromodomain and extraterminal bet domain family are epigenetic readers that bind.
A firstinclass p300cbp bromodomain inhibitor for the. Bet bromodomain proteins brd2, brd3 and brd4 selectively. Targeting the ewsets transcriptional program by bet. The bet proteins utilize bromodomains to interact with acetylated histone tails and mediate downstream functions, such as histone acetylation recognition, chromatin remodeling. Crystallographic study showed extensive hydrogen bond interactions formed in the kac pocket of brpf1 upon binding of 42. Specific bet bromodomain inhibitors to treat disease. Generation of a selective small molecule inhibitor of the cbp. European journal of medicinal chemistry 2019, 182, 111633. Integration of genetic features with chemosensitivity data.
Zen3365 is novel and selective bet inhibitor that binds bet bromodomains in vitro and displaces bet proteins from chromatin in cells 2. We demonstrate that cbp30 inhibits il17a production in primary human cells and th17 responses from patients with as and psa. The bet bromodomain inhibitor, jq1, facilitates cflip degradation and enhances trailinduced apoptosis independent of brd4 and cmyc inhibition weilong yao1,2, ping yue2, fadlo r. The selective inhibition of 42 on brpf1 over other bromodomains was demonstrated by both biochemical assay and isothermal titration calorimetry. Bmediated processes, such as t cell activation and differentiation. Delmore je, issa gc, lemieux me, rahl pb, shi j, jacobs hm, kastritis e. Initially it was shown that jq1 could block the growth of a rare, aggressive form of human squamous carcinoma with brd4nut translocation 24 as well as of myc. In experimental models of multiple myeloma, a mycdependent hematologic malignancy, jq1.
Otx015 is under evaluation in expansion cohorts using this intermittent administration 14 days every 3 weeks to allow for recovery from toxic effects. Rvx208, an inhibitor of bet transcriptional regulators. Spatially constrained tandem bromodomain inhibition. Bromodomains are protein interaction domains with predicted good druggability 18, which has been demonstrated by potent and selective inhibitors developed for the bet bromo and extracellular domain family of transcriptional regulators. Oct 24, 2016 the ability of bet inhibitors to effect inhibition of armediated signaling 16 and er. Inhibition of brd4 leads to selective repression of these genes. Acetylation of lysine residues in histone tails plays an important role in the regulation of gene transcription. Benzoxazinonecontaining 3,5dimethylisoxazole derivatives as.
Bet bromodomain proteins, brd2, brd3, and brd4 were found to be downregulated. To date, however, genomic biomarkers to direct clinical translation have been lacking. Thus, bet bromodomain inhibition results in the combined and selective suppression of several key t h 17 lineageassociated genes, such as il17, il21, gmcsf, il22, and il23r. The bromodomain and extraterminal bet protein brd4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. May 18, 2017 this contrasts with the finding that the selective inhibition of human bet bd2 in liver cancer cells induced only minor effects on transcriptional regulation 43 and that bd1 plays a more important. Crebbpep300 bromodomains are critical to sustain the gata1. Inhibition of bet recruitment to chromatin as an effective treatment for mllfusion leukaemia mark a. Development and utilization of bromodomain and extra. Selective inhibition of tumor oncogenes by disruption of. Inhibition of bet bromodomains researchers create first molecule blocks key component of cancer genes onoff switch. Bromodomain inhibitor otx015 in patients with acute. One of the new compounds, r12 y02234, binds to brd41 with a k d value of 110 nm and blocks bromodomain and acetyl lysine interactions with an ic 50 value of 100 nm. The bromodomain and extra terminal domain bet family of bromodomains brds are wellknown drug targets for many human diseases.
Hickman tt, felletar i, philpott m, munro s, mckeown mr, wang y, christie al, west n, et al. Rwth technology highly efficient and selective inhibitors. Inhibition of bet recruitment to chromatin as an effective treatment for mllfusion leukaemia. Small molecule bet inhibitors, such as jq1, block bet protein binding to acetylated lysines, but lack selectivity within the bet family brd2, brd3, brd4, brdt, making it difficult to. An efficient and selective inhibition of the bet proteins is therefore of great importance for cancer therapies. The bromodomain and extraterminal bet proteins are a bromodomain subfamily that includes brd2, brd3, brd4, and brdt. Specific inhibitors of bet proteins such as ibet151 or jq1 resulted in displacement of brds from chromatin and inhibition of transcription at key genes such as bcl2, myc, and cdk6. The profound biology associated with bet bromodomain inhibition has provided a convincing rationale for targeting bromodomains for the treatment of disease. Deciphering the mechanisms of selective inhibition for the tandem. Targeting myc dependence in cancer by inhibiting bet.
Pharmacological inhibition of bromodomaincontaining proteins in inflammation. In this work, we show that cbp30 is a highly selective inhibitor of the bromodomains of the transcriptional coactivators cbp and p300. The oncedaily recommended dose for oral, single agent oral otx015 in patients with lymphoma is 80 mg on a 14 days on, 7 days off schedule, for phase 2 studies. Prinjha3, antje dittmann4, george giotopoulos1, marcus bantscheff4, waiin chan1, samuel c. Selective inhibition of the plateletderived growth factor signal transduction pathway by a protein. Because of this, there is strong evidence for targeting bet bromodomains as. The binding of bet protein bromodomains to chromatin regulates gene expression and small molecule inhibition of that binding produces selective effects on gene expression. Bet bromodomains, resulting in the release of bet proteins from chromatin 7, 8. Identification of a chemical probe for bromo and extra c. Spatially constrained tandem bromodomain inhibition bolsters.
Allelespecific chemical genetics enables selective inhibition within families of highlyconserved proteins. The reported antitumor activity of the bet family bromodomain inhibitors has prompted the development of inhibitors against other bromodomains. Clinical progress and pharmacology of small molecule. Because bet bromodomain inhibition results in the suppression of a subset of nf. Significantly fewer genes are altered after ccs1477 vs. Selective inhibition of the bd2 bromodomain of bet. Dawson ma, prinjha rk, dittmann a, giotopoulos g, bantscheff m, chan wi.
Structurebased discovery of selective brpf1 bromodomain. Jul, 2014 acetylation of lysine residues in histone tails plays an important role in the regulation of gene transcription. Apoa1 expression is regulated by bet proteins, and chemical inhibition of bet bromodomains has been associated with apoa1 upregulation on transcriptional and protein levels 9, 31, 32. Selective inhibition of the bromo and extra cterminal domain bet family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and antiinflammatory properties of such inhibitors. Assessing cellular efficacy of bromodomain inhibitors using. We conducted a cellbased screen of genetically defined cancer cell lines using a prototypical inhibitor of bet bromodomains. Selective inhibition of bet bromodomains by small molecule inhibitors has emerged as a promising therapeutic strategy for the treatment of cancer. Jq1 in parental 22rv1 cells ccs1477 binds to the conserved bromodomain of p300 and cbp 1. Bromodomains are acetyllysine binding pockets that target bromodomaincontaining proteins to histones and thereby affect chromatin structure and function. Otx015 is under evaluation in expansion cohorts using this intermittent administration 14 days every 3. Displacement of bromodomain and extraterminal bet proteins from chromatin has promise for cancer and inflammatory disease treatments, but roles of bet proteins in metabolic disease remain unexplored. Abbv744, a selective inhibitor of the bd2 domains of bet family proteins, is effective against prostate cancer in mouse xenograft models, with lower toxicities than the dualbromodomain bet.
Discovery, structural insight, and bioactivities of by27 as a selective inhibitor of the second bromodomains of bet proteins. Brd9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition natalie h. Zen3365 inhibits beti specific gene signature in multiple matrices including myc and bcl2 3. Jq1 is a thienotriazolo1,4diazepine that displaces bet bromodomains from chromatin by competitively binding to the acetyllysine recognition pocket. Deciphering the mechanisms of selective inhibition for the. The active pockets of the two tandem bromodomains bd1bd2 are highly conserved sequence similarity is about 95%, thus it is of great medical importance and still a significant challenge to develop bd1bd2 selective inhibitors.
Motivated by the above rationale, we have developed biochemical platforms. Bromodomain inhibitor otx015 in patients with acute leukaemia. The role of bromodomains in transcriptional regulation directly influences numerous disease. We report that the bromodomains of the histone acetyltransferases crebbpep300 are critical to sustain the proliferation of human leukemia and. One important factor to consider is that inhibition of the bet bromodomains leads to signi. Motivated by the above rationale, we have developed biochemical platforms for the.
Zen3365 is a novel bet bromodomain inhibitor for the. Bet bromodomain inhibition suppresses th17mediated. The inhibitor jq1 was synthesized in both racemic and enantiomerically pure. Bet proteins are important because they regulate normal transcription processesboth as well as the transcription of oncogenes such as cmyc and bcl 2 in various types of cancer. The ability of cbp30 to inhibit il17a secretion was identified using an unbiased screen of primary human cells biomap. Bet inhibitors have been described that are able to discriminate between the first and second bromodomains of bet proteins bd1 vs bd2. A major collaborative focus of our research groups concerns the development of chemical probes18, 19 and the optimization of therapeutic leads for the translation of smallmolecule modulators of epigenetic targets as cancer therapeutics.
Jq1 is the stereoisomer of jq1, a cellpermeable smallmolecule inhibitor of bet bromodomain that competitively binds to acetyllysine recognition motifs. Bet inhibition by jq1 downregulates myc transcription, followed by genomewide downregulation of mycdependent target genes. In a mouse model of myeloma, treatment with nmp demonstrated antineoplastic and immunomodulatory activity consistent with bet inhibition. Inhibition of bromodomain and extraterminal bet proteins. Selective inhibition of the bd2 bromodomain of bet proteins. Bet bromodomain inhibition suppresses transcriptional. Vishwa deepak, binglin wang, dwayne koot, abe kasonga, xiao xing stander, magdalena coetzee, andre stander. A selective and potent inhibitor of bet family bromodomains. Request pdf potent and selective bivalent inhibitors of bet bromodomains proteins of the bromodomain and extraterminal bet family, in particular bromodomaincontaining protein 4 brd4, are. We report the design, synthesis and evaluation of a new series of benzoxazinonecontaining 3,5dimethylisoxazole derivatives as selective bet inhibitors. Only in the research context has targeting individual bet proteins been. The bromodomains and extraterminal domain bet family proteins recognize acetylated chromatin through their bromodomains bds and help in regulating gene expression. Bromodomain inhibitor otx015 in patients with lymphoma or.
Bet bromodomain inhibition suppresses th17mediated pathology. Selective bet bromodomain inhibition as an antifungal therapeutic strategy. Bet bromodomain inhibition as a therapeutic strategy in. Pdf selective inhibition of bet bromodomains researchgate. The active pockets of the two tandem bromodomains bd1bd2 are highly conserved sequence similarity is about 95%, thus it is of great medical importance and still a significant 2017 pccp hot articles. Data for the nonleukaemia cohort are published elsewhere. Moreover, they are increasingly being recognised as important mediators of a wide range of diseases. Once bound, these bromodomains recruit protein complexes involved in chromatin structure regulation, and thus play a role in gene expression. Selective inhibition of the bd2 bromodomain of bet proteins in. Generation of a selective small molecule inhibitor of the. The recent discovery 2010 of potent and highly specific small molecule inhibitors for the bet family of bromodomains beti, such as the triazolodiazepinebased jq1 and the quinolonebased bet protein inhibitor ibet151 among others, has shown that these molecules are able to bind to the kac binding pocket of the bromodomains and disrupt.
Selective inhibition of bet bromodomains johns hopkins. Cbp30, a selective cbpp300 bromodomain inhibitor, suppresses. Selective inhibition of bet bromodomains international nut. Targeting the ewsets transcriptional program by bet bromodomain inhibition in ewing sarcoma. Pharmacological targeting of brd4 bromodomains by small molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth andor survival. There are 57 bromodomains, with bromodomain and extraterminal bet being a subset that is currently a. Progress in the development of nonbet bromodomain chemical. Targeting mycn in neuroblastoma by bet bromodomain inhibition. To ascertain that selective inhibitors tested in frap experiments do not crossreact with other bromodomains in the cellular environment, the bet inhibitor pfi1 was profiled across 10 bromodomain targets in frap assays at 1. The bromodomain and extraterminal bet protein family includes. Bdependent genes in murine macrophages nicodeme et al.
Bet bromodomains are of particular interest, as they are attractive therapeutic. Zen3365 synergizes with cytarabine and flt3 inhibitor ac220 to inhibit mv411 cell proliferation 4. This file contains supplementary methods including the compound synthesis route and characterization data, supplementary figures 12 and. Bdependent gene expression is one canonical pathway suppressed by bet inhibitors 7. Jq1 is a novel thienotriazolo1,4diazepine with an appended and bulky tbutyl ester functional group at c6 position in its chemical structure, which allows for additional pendant group. Selective bet bromodomain inhibition as an antifungal.
As a consequence, a similar mode of action has also been suggested for rvx208, but no data characterizing the rvx208bet interaction have been published so far. Selective bromodomain inhibitors that disrupt the binding of bet proteins to histones have recently been described7,8. Bet bromodomain inhibition as a novel strategy for reactivation of hiv1 camellia banerjee, nancie archin, daniel michaels, anna c. Khuri2 and shiyong sun2 1 department of respiration, xiangya hospital and xiangya school of medicine, central south university, changsha, hunan, pr china 2. Accordingly, bet inhibitors were found to be therapeutically effective in preclinical animal models of endotoxic shock caused by acti. Bet bromodomain inhibition promotes neurogenesis while. However, the human genome encodes more than 60 different bromodomains and most of them remain unexplored. Inhibitors with selectivity for the first or second bromodomain are desired to aid. Expression of key inflammatory genes are downregulated by inhibition of bet bromodomains, conferring protection against endotoxic shock and bacteriainduced sepsis. Aug 25, 2015 here, we show the potent and selective nature of inhibition of the cbpp300 bromodomains by cbp30.
Discovery of i brd9, a selective cell active chemical probe. However, no bet inhibitor has yet been described that can reliably distinguish between bet family members brd2 vs brd3 vs brd4 vs brdt. Inhibition of bet recruitment to chromatin as an effective. A selective and potent inhibitor for the bet subfamily of bromodomains.
Boston in the quest to arrest the growth and spread of tumors, there have been many attempts to get cancer genes to ignore their internal instruction manual. Ccs1477 is a potent and selective inhibitor of p300cbp bromodomains ccs1477 p300cbp kd nm 1. Assessing cellular efficacy of bromodomain inhibitors. Bet bromodomain inhibition as a therapeutic strategy to. Suppression of il21 results in impaired stat3 activation, and in rorc and batf expression. Using a selective smallmolecule bromodomain inhibitor, jq1, we identify bet bromodomain proteins as regulatory factors for cmyc. Here we report a selective and highly potent chemical probe compound targeting the bromodomains of cbpp300. Rvx297 is a 4quinazolinone derivative related to rvx208 with an alkylpyrrolidine side chain off the dimethyl substituted phenyl ring fig.
However, the bet family represents just 8 of the 56 human bromodomains. Delmore je, issa gc, lemieux me, rahl pb, shi j, jacobs hm. A selective and potent inhibitorof bet family bromodomains. Targeting cancer with a novel bet bromodomain inhibitor orion. Potent and selective bivalent inhibitors of bet bromodomains. Bet bromodomains are of particular interest, as they are attractive therapeutic targets but existing inhibitors are pan selective. These effects are not easily assessed in patients with acute leukaemia.
375 1081 1042 1008 1492 862 989 622 582 353 685 762 167 1255 784 412 210 987 1356 1179 16 1336 463 1139 441 451 849 1106 1565 416 1342 824 89 152 246 504 852 895 636