Selective inhibition of acetyllysine effector domains of the bromodomain family in oncology. A selective and potent inhibitor of bet family bromodomains. The bromodomains and extraterminal domain bet family proteins recognize acetylated chromatin through their bromodomains bds and help in regulating gene expression. This compound binds with an affinity in the low micromolar range yet exerts suitable unexpected selectivity in vitro against the other members of the bromodomain and extraterminal domain bet family. A selective and potent inhibitor for the bet subfamily of bromodomains.
The bet bromodomain inhibitor, jq1, facilitates cflip. Bet bromodomain proteins regulate myc transcription. The four bet bromodomains brd2, brd3, brd4, and brdteach contain two bromodomain modules. Bet bromodomain inhibition as a therapeutic strategy in ovarian cancer by downregulating foxm1. Brd41 his bromodomain containing protein 4, bromodomain 1. Higherthroughput, labelfree, realtime molecular interaction analysis. Bet bromodomain inhibition suppresses graftversushost. Chemical modulation of chromatin structure jun qi danafarber cancer institute, boston, massachusetts 02115 correspondence. European journal of medicinal chemistry 2019, 182, 111633. Discovery, structural insight, and bioactivities of by27 as a selective inhibitor of the second bromodomains of bet proteins. Targeting cancer cells with bet bromodomain inhibitors yali xu and christopher r.
Selective inhibition of bet bromodomains europe pmc. Antiinflammatory effects of bromodomain and extraterminal. Shen y, smith wb, fedorov o et al 2010 selective inhibition of bet bromodomains. We report the discovery and characterization of rvx208 as a domain selective inhibitor of bets. A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the nterminal tails of histones. Xdmcbp is a highly potent and selective inhibitor for the bromodomains of cbp and p300 derived from a pan selective bet brdbinding fragment. Bromodomains are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation. Motivated by the above rationale, we have developed biochemical platforms for the. To further investigate the effect of bet protein inhibition on t cell differentiation, we used jq1 as a representative probe that did not interfere with overall t cell viability or proliferation at 0.
Rvx297 is structurally related to the clinical compound rvx208, currently undergoing phase iii clinical trials for the treatment of cardiovascular diseases, but is distinctly different in its biological and pharmacokinetic profiles. Please note that tocris will only send literature to established scientific business institute addresses. The human proteome comprises 46 bromodomaincontaining proteins with a total of 61 bromodomains, which, despite highly conserved structural features, recognize a wide array of natural peptide ligands. Selective bet bromodomain inhibition as an antifungal therapeutic. The bet bromodomain inhibitor, jq1, facilitates cflip degradation and enhances trailinduced apoptosis independent of brd4 and cmyc inhibition weilong yao1,2, ping yue 2, fadlo r. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. The bromodomain and extra terminal domain bet family of bromodomains brds are wellknown drug targets for many human diseases. Selective inhibition of bet bromodomains pubmed central pmc. Bromodomain and extraterminal domain bet proteins help direct the differentiation of helper t cell subsets, but their role in activated t cell function has not been described in detail.
However, because the bromodomains of bet proteins share 75% identity between family members, more selective perturbations of bet protein function may improve therapeutic efficacy in the future. Jq1 is the stereoisomer of jq1, a cellpermeable smallmolecule inhibitor of bet bromodomain that competitively binds to acetyllysine recognition motifs. To explore the individual functional contributions of the first bd1 and second bd2 bromodomains in biology and therapy, we developed selective bd1 and bd2 inhibitors. Smallmolecule inhibitor jq1 effect on multiple myeloma. Bryant, peter sandy, srividya balasubramanian, deanna a. Selective targeting of bd1 and bd2 of the bet proteins in cancer and. Jq1 is a novel thienotriazolo1,4diazepine with an appended and bulky tbutyl ester functional. Bet bromodomain inhibitors with onestep synthesis discovered. In the lipopolysaccharide lps model of inflammation, rvx297 reduced proinflammatory. Development of a first in class inhibitor of bet 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. The bromodomain and extraterminal domain bet family of proteins bind acetylated lysine residues on histone proteins. Bet bromodomains will facilitate elucidation of their precise biological roles and potentially lead to the development of new medicines. Using a selective smallmolecule bromodomain inhibitor, jq1, we identify bet bromodomain proteins as regulatory factors for cmyc.
Read rvx297 a novel bd2 selective inhibitor of bet bromodomains, biochemical and biophysical research communications on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available. A 110amino acid protein domain which recognises acetylated lysine residues on the nterminal tails of histone. Bromodomains are readers that bind acetylated lysines in histone tails. Crystal structures of the bdf1 bds reveal binding modes for these inhibitors that are sterically incompatible with the human betbinding pockets. The genomes of eukaryotic organisms are highly organized within the nucleus of the cell.
Bet proteins as targets for anticancer treatment cancer. Sep 11, 2014 the present invention relates to bet bromodomain inhibitors and to therapeutic methods of treating conditions and diseases wherein inhibition of bet bromodomains provides a benefit. 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. Jci bet bromodomain inhibition enhances t cell persistence. Here, we examine structure activity relationships within the bi2536 plk1 kinase inhibitor scaffold, previously reported to bind brd4. Apr 29, 2016 the bromodomains and extraterminal domain bet family proteins recognize acetylated chromatin through their bromodomains bds and help in regulating gene expression. Pfi1, a highly selective protein interaction inhibitor. The surprising efficacy of these pan bet inhibitors in mouse models of various diseases, including cancer, led to rapid translation into the clinic. Bet inhibitors have been described that are able to discriminate between the first and second bromodomains of bet proteins bd1 vs bd2.
Bromodomains brd are protein interaction modules that. Initial screening against 10 bromodomains suggested selectivity for cbpp300 bromodomains. Therefore, the development of chemical probes for non. Development of a first in class inhibitor of bet bromodomains and dopamine receptor 2. Selective inhibition of bet bromodomains international nut. Bet bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the bet. The high similarity between bromodomain proteins of the bet family makes development of selective and specific inhibitors both difficult and necessary. Inhibition of bromodomain and extraterminal proteins bet. Discovery, structural insight, and bioactivities of by27. Selective inhibition of the bd2 bromodomain of bet. Alpha screen assays have shown that pfi1 displaces histone 4 peptide acetylated at lysines k5, k8, k12, and k16 h4k5 ac k8 ac k12 ac k16 ac with a potency ic 50.
However, jq1 has a very short halflife and dose concentrations required to mediate single agent activity are above physiologic safety levels in vivo 69. 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. Rvx208 provides proofofconcept that selective inhibition within the bet family is feasible picaud et al. Khuri and shiyong sun 1 department of respiration, xiangya hospital and xiangya school of medicine, central south university, changsha, hunan, pr china. Jul 11, 2018 a new small molecular inhibitor, jq1, targeting brd4, which recognizes the acetylated lysine residues, has been shown to induce cell cycle arrest in different cancers by inhibiting myc oncogene. The effect of this inhibitor is far more selective than that observed for the pan bet bromodomain inhibitor jq1. Selective inhibition of bet bromodomains researchgate. Recent reports have highlighted the dual bromodomains of taf1 taf11,2 as synergistic with bet inhibition in cellular cancer models, engendering interest in taf bet polypharmacology. Selective targeting of bd1 and bd2 of the bet proteins in. To explore the individual functional contributions of the first bd1 and second bd2 bromodomains in biology and therapy, we developed selective. Therefore, we propose that bet inhibitors might represent a viable.
A previously identified bet inhibitor also inhibited other bromodomain containing proteins and p38. Supplementary procedures, supplementary tables 15 and additional references. However, the downstream signaling of myc inhibition induced by bet inhibitor is not well understood. For example the bet protein brd4 interacts with superenhancer regions, regulating cmyc expression, a protein that is implicated in as many as 50% of all cancers. A midthroughput screening followup program targeting the first bromodomain of the human brd4 protein, brd4bd1, identified an acetylatedmimic xanthine derivative inhibitor. Makoto yoshioka 1, jay chauhan2, sara grantham1, steven fletcher2, jeffrey w. The potent pan bet bromodomain inhibitor jq1 was key to delineating mechanism of action and establishing proof of principle of bet inhibition.
Selective bromodomain protein inhibitors that reduce. Rvx297 preferentially binds to the bd2 domains of the bet bromodomain and extra terminal bet. Sep 24, 2010 a new approach is used to target bet family bromodomains which are found in transcriptional regulators where they mediate the recognition of acetyllysine chromatin marks. After the development of firstin class bet bromodomain inhibitors. Tocris offers the following scientific literature for bromodomains to showcase our products. Human cells contain tens of thousands of active promoter regions and enhancer regions that are highly celltype dependent, and a few hundred superenhancers, which are clusters of enhancers characterized by a very high binding of mediator complexes and master transcription factors. Selective inhibition of bet bromodomains by small molecule inhibitors has emerged as a promising therapeutic strategy for the treatment of cancer. Interestingly, unlike other bet inhibitors, rvx208 binds preferentially to the bd2 domain of brd2 and brd3 proteins. Along with xray crystalstructure analysis and thermodynamic profiling, xdm. Bromodomain and extraterminal domain inhibitors beti for cancer therapy.
Bet bromodomain inhibition as a novel strategy for. May 18, 2017 bet proteins bind chromatin through their bromodomains bds to regulate transcription and chromatin remodelling. Here, we show the potent and selective nature of inhibition of the cbpp300 bromodomains by cbp30. 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. Targeting myc dependence in cancer by inhibiting bet bromodomains. The reported inhibitors were prepared from simple starting materials in two steps followed by separation of the regioisomers or regios. M in our experimental system supplemental figure 4, a and b.
Bet bromodomain inhibition in prostate cancer treatment. Dual inhibition of taf1 and bet bromodomains from the bi. Khuri2 and shiyong sun2 1 department of respiration, xiangya hospital and xiangya school of medicine, central south university, changsha, hunan, pr china 2. In this study, we report the discovery of a potent and selective bet bd2 inhibitor. Pdf benzodiazepines and benzotriazepines as protein. Zhang z, ma p, jing y, yan y, cai mc, zhang m, zhang s, peng h, ji zl, di w, gu z, gao wq, zhuang g. Discovery and characterization of covalent bet bromodomain. Their most important function is the regulation of gene transcription by the recruitment of different molecular partners.
Selective bet bromodomain inhibition as an antifungal. Deciphering the mechanisms of selective inhibition for the. Rvx297 a novel bd2 selective inhibitor of bet bromodomains. However, because of the highly conservation of its two homologous bromodomains bd1bd2, selective inhibition of each bromodomain remains a challenge. Discovery of tetrahydroquinoxalines as bromodomain and. Inhibition of bet bromodomains researchers create first molecule blocks key component of cancer genes onoff switch. So far, successful efforts have been limited to chromatin modifying enzymes, or socalled epigenetic writers and erasers. Exploring selective inhibition of the first bromodomain of. Evaluation of 124 animals given birth to to eighteen dams diagnostically positive for contamination with showed that there was a.
Selective inhibition of bet bromodomains johns hopkins. Inhibition of bromodomain and extraterminal proteins bet as a potential therapeutic approach in haematological malignancies. Only in the research context has targeting individual bet proteins been. Simple 1substituted 5 and 6isoxazolylbenzimidazoles have been shown to be potent inhibitors of the bet bromodomains with selectivity over the related bromodomain of cbp. Bet inhibitors are a class of drugs that reversibly bind the bromodomains of bromodomain and. Targeting cancer cells with bet bromodomain inhibitors. 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. Nature 2010928 selective inhibition of bet bromodomains. Selective inhibition of acetyllysine effector domains of. However, no bet inhibitor has yet been described that can reliably distinguish between bet family members brd2 vs brd3 vs brd4 vs brdt. Read selective inhibition of bet bromodomains, nature on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at.
Here, the authors show that the bet protein bdf1 is essential for the fungal. Rvx297, a bet bromodomain inhibitor, has therapeutic. Bromodomain and extraterminal domain inhibitors beti for. Bet bromodomain inhibition as a novel strategy for reactivation of hiv1 camellia banerjee, nancie archin, daniel michaels, anna c. Bet inhibition by jq1 downregulates myc transcription, followed by genomewide downregulation of mycdependent target genes. Jan 27, 2016 the highly specific bet inhibitor, ibet762, was evaluated on myc expression in prostate cancer models. Targeting myc dependence in cancer by inhibiting bet bromodomains jennifer a. This observation may have clinical implications in cancer, for instance the development.
Pfi1 is a potent and selective bet bromodomain inhibitor. Bet proteins serve to regulate the expression of importance oncogenes, including those involved in apoptosis as well as cell cycle progression. Bet bromodomain inhibition promotes derepression of txnip. The two tandem bromodomains of the bet proteins enable chromatin binding to facilitate transcription. Dec 23, 2010 a selective and potent inhibitor for the bet subfamily of bromodomains. Bet bromodomain inhibition suppresses th17mediated. Inhibition of bet bromodomains as a therapeutic strategy for. Potent and selective bivalent inhibitors of bet bromodomains. Dec 24, 2019 data availability statementall data have already been placed into research gate at this url.
Bet bromodomain inhibition suppresses human t cell. Bet inhibitors are small molecules that specifically bind bromodomains, preventing bet proteins from binding to chromatin. Bet bromodomain inhibition as a therapeutic strategy to target c. Gene regulation is fundamentally governed by reversible. 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. Bet bromodomain inhibition by jq1 confers a selective repression of. Ibet762 potently reduced myc expression in prostate cancer cell lines and a patientderived tumor model with subsequent inhibition of cell growth and reduction of tumor burden in vivo. We report an easily synthesized dihydropyridopyrimidine pan bet inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Chemical inhibition of epigenetic regulatory proteins brdt and brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. Bet bromodomain inhibition as a therapeutic strategy in. We demonstrate that cbp30 inhibits il17a production in primary human cells and th17 responses from patients with as and psa.
Results and discussion selective bet inhibitor ibet11 provided compelling evidence for targeting bet bromodomains in in. Bromodomains, as the readers of lysine acetylation, are responsible in transducing the signal carried by acetylated lysine residues and translating it into various normal or abnormal phenotypes. Bromodomain definition of bromodomain by medical dictionary. Selective targeting of bd1 and bd2 of the bet proteins in cancer. Rvx208, an inhibitor of bet transcriptional regulators. Download highres image open in new tab download powerpoint. Download hires image download to mspowerpoint cite this. Cbp30, a selective cbpp300 bromodomain inhibitor, suppresses. Inhibition of bet bromodomains as a therapeutic strategy. Recently, selective inhibition of bet bd2 is emerging as a promising strategy for drug discovery. In experimental models of multiple myeloma, a mycdependent hematologic malignancy, jq1. Targeting cancer with a novel bet bromodomain inhibitor. Allelespecific chemical genetics enables selective inhibition within families of highlyconserved proteins. Inanticipation of clinical drug resistance to bet bromodomain inhibition, we identified an epigenetic mechanism of resistance in which hyperphosphorylation of bet bromodomains enables tumor cells to recruit these proteins to chromatin independent of bromodomain activity shu et al.
In this study, we investigate various consequences of epigenetic perturbation in human t lymphocytes using mk8628, a potent and highly selective inhibitor of bet. Inhibition of bet bromodomains as a therapeutic strategy for cancer drug discovery leilei fu 1, mao tian, xiang li, jingjing li1, jian huang2, liang ouyang1, yonghui zhang1,3 and bo liu1 1 state key laboratory of biotherapy, collaborative innovation center of biotherapy, department of urology, west china hospital, sichuan university. Moreover, proteins containing bromodomains are also epigenetic regulators, although little is known about the specific function of these domains. Pdf selective inhibition of bet bromodomains researchgate.
Selective inhibition of bet bromodomains, nature 10. Additionally, we show that the covalent interaction with bet bromodomains is timedependent and can be monitored by thermodenaturation assay as a distinct peak from the noncovalent inhibitors. As a member of the bromodomain and extraterminal domain bet family, brd4 is considered as a potential target for cancer treatment. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets. Rvx297, a bet bromodomain inhibitor, has therapeutic effects in. Pdf epigenetic proteins are intently pursued targets in ligand discovery. Bromo and extraterminal bet proteins have diverse roles in regulating tissuespecific transcriptional programs, raising safety concerns for their inhibition and suggesting that targeting of specific isoforms or even specific domains within this subfamily is important. Having demonstrated potent, selective binding to brd4 in homogeneous and. Viability was assessed by comparing each condition to their respective drug free controls. Computational study on the selective inhibition mechanism. Abbv744, a selective inhibitor of the bd2 domains of bet family proteins, is effective against prostate cancer in mouse xenograft models, with. We invite you to request or download your copy today. Because cmyc is known to regulate promoterproximal pause release of pol ii, also through the recruitment of ptefb, we evaluated the selective smallmolecule inhibitor of bet bromodomains, jq1, as a chemical probe to interrogate the role of bet bromodomains in mycdependent transcription and to explore their role as therapeutic targets in c. Despite significant progress in this area, systematic studies of selective bet bd2 inhibitors are still few.
Jul 21, 2016 interestingly, two recent reports demonstrated that airway smooth muscle cells are sensitive to bet regulation 31, 32, suggesting that bet inhibition could have effects on a variety of cell types in vivo and a synergistic effect could be seen in bet inhibition therapy. Bet bromodomain inhibition as a therapeutic strategy to. In this study, we evaluated the antitumor activity of odm207, a novel, potent and highly selective bet bromodomain inhibitor. However, non bet bromodomains such as those in p300 and cbp are less studied. Selective inhibition of brdt by a small molecule is an exciting new target in the search for a. It is present in over 100 proteins, especially chromatinassociated proteinse. The bromodomain and extraterminal bet family proteins associate with transcriptional activation through interaction with acetylated chromatin, therefore playing a key role as epigenetic regulators. Pfi1, a highly selective protein interaction inhibitor, targeting bet. Download figure open in new tab download powerpoint.