Identification of a novel series of BET family bromodomain inhibitors: Binding mode and profile of I-BET151 (GSK1210151A)

Seal, Jonathan; Lamotte, Yann; Donche, Frédéric; Bouillot, Anne; Mirguet, Olivier; Gellibert, Françoise; Nicodème, Edwige; Krysa, Gaël; Kirilovsky, Jorge; Beinke, Sören; McCleary, Scott; Rioja, Inma; Bamborough, Paul; Chung, Chun‐wa; Gordon, Laurie J.; Lewis, Toni; Walker, Ann L.; Cutler, Leanne; Lugo, David; Wilson, David M.; Witherington, Jason; Lee, Kevin; Prinjha, Rab K.

doi:10.1016/j.bmcl.2012.02.041

Cited by 189 publications

(175 citation statements)

References 8 publications

Supporting

Mentioning

169

Contrasting

Order By: Relevance

“…I-BET151 is a selective and potent inhibitor of BET proteins, displacing them from chromatin by competing with histone and nonhistone acetyllysine residues for bromodomain binding (24).…”

Section: Resultsmentioning

confidence: 99%

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Yoshida

Bansal

Schaefer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Aire controls immunologic tolerance by inducing a battery of thymic transcripts encoding proteins characteristic of peripheral tissues. Its unusually broad effect is achieved by releasing RNA polymerase II paused just downstream of transcriptional start sites. We explored Aire's collaboration with the bromodomaincontaining protein, Brd4, uncovering an astonishing correspondence between those genes induced by Aire and those inhibited by a small-molecule bromodomain blocker. Aire:Brd4 binding depended on an orchestrated series of posttranslational modifications within Aire's caspase activation and recruitment domain. This interaction attracted P-TEFb, thereby mobilizing downstream transcriptional elongation and splicing machineries. Aire:Brd4 association was critical for tolerance induction, and its disruption could account for certain point mutations that provoke human autoimmune disease. Our findings evoke the possibility of unanticipated immunologic mechanisms subtending the potent antitumor effects of bromodomain blockers.

show abstract

“…I-BET151 is a selective and potent inhibitor of BET proteins, displacing them from chromatin by competing with histone and nonhistone acetyllysine residues for bromodomain binding (24).…”

Section: Resultsmentioning

confidence: 99%

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Yoshida

Bansal

Schaefer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…30 Several structure/activity-based BET protein bromodomain antagonists (BAs) have been developed, including JQ1 and I-BET151, which displace the BET proteins, including BRD4 and the associated pTEFb from the acetylated chromatin. [31][32][33] This results in the transcriptional repression of BCL-2, c-MYC, cyclin D1, and CDK6, as well as induces growth arrest and apoptosis of leukemia cells. [34][35][36] Pertinent to this, we had previously reported that cotreatment with JQ1 and histone deacetylase inhibitor (HDI) is synergistically lethal against acute myeloid leukemia (AML) cells.…”

mentioning

confidence: 99%

Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib

Sun

Shah

Fiskus

et al. 2015

Blood

View full text Add to dashboard Cite

Key Points• BA reduces MYC, CDK4/6, nuclear RelA, and BTK expression and is synergistically lethal with ibrutinib in MCL cells.• Cotreatment with BA and inhibitor of BCL2, CDK4/6, or histone deacetylases is synergistically lethal against ibrutinib-resistant MCL cells.Mantle cell lymphoma (MCL) cells exhibit increased B-cell receptor and nuclear factor (NF)-kB activities. The bromodomain and extra-terminal (BET) protein bromodomain 4 is essential for the transcriptional activity of NF-kB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and cyclindependent kinase (CDK)4/6, inhibits the nuclear RelA levels and the expression of NF-kB target genes, including Bruton tyrosine kinase (BTK) in MCL cells. Although lowering the levels of the antiapoptotic B-cell lymphoma (BCL)2 family proteins, BA treatment induces the proapoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Cotreatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared with each agent alone, cotreatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells, which overexpress CDK6, BCL2, Bcl-xL, XIAP, and AKT, but lack ibrutinib resistanceconferring BTK mutation. Cotreatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL. (Blood. 2015;126(13):1565-1574 Introduction Among the genetic alterations described in mantle cell lymphoma (MCL) cells are those that involve p53, cyclin-dependent kinase (CDK)4, CDKN2A, MYC, B-cell lymphoma (BCL)2, B-cell receptor (BCR), and nuclear factor (NF)-kB signaling genes. [1][2][3] These genetic alterations confer a cell autonomous pro-growth and pro-survival advantage on the MCL cells, which is especially dependent on NF-kB, BCL2, and MYC activities. [2][3][4] Next generation sequencing has also disclosed new targets for therapeutic intervention in the deregulated molecular signaling through BCR, toll-like receptor, NOTCH, NFkB, and mitogen-activated protein kinase signaling pathways in the MCL cell lines and patient-derived primary MCL.3-7 Pre-clinical and clinical studies have shown that ibrutinib, a selective, orally bioavailable, irreversible inhibitor of Bruton tyrosine kinase (BTK) in the BCR, also inhibits NF-kB activity and is active against B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and MCL. 6,8 Ibrutinib has demonstrated impressive clinical efficacy and is approved for the treatment of CLL and MCL.9-11 Despite its high level of clinical activity, primary or acquired clinical resistance to ibrutinib therapy is commonly observed....

show abstract

“…10). In addition, prompted by this, several structure/ activity-based BET protein small-molecule inhibitors have been developed, including JQ1 and I-BET151 (IB), which displace the BET proteins, along with the associated transcript initiation and elongation factors, from the chromatin (11)(12)(13). This results in transcriptional repression of BCL2, c-MYC, and CDK6 as well as induces growth arrest and apoptosis of AML cells (14,15).…”

Section: Introductionmentioning

confidence: 99%

Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

Fiskus

Sharma

et al. 2014

Molecular Cancer Therapeutics

172

170

View full text Add to dashboard Cite

The bromodomain and extra-terminal (BET) protein family members, including BRD4, bind to acetylated lysines on histones and regulate the expression of important oncogenes, for example, c-MYC and BCL2. Here, we demonstrate the sensitizing effects of the histone hyperacetylation-inducing pan-histone deacetylase (HDAC) inhibitor panobinostat on human acute myelogenous leukemia (AML) blast progenitor cells (BPC) to the BET protein antagonist JQ1. Treatment with JQ1, but not its inactive enantiomer (R-JQ1), was highly lethal against AML BPCs expressing mutant NPM1cþ with or without coexpression of FLT3-ITD or AML expressing mixed lineage leukemia fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of c-MYC and BCL2 and reduced their levels in the AML cells. Cotreatment with JQ1 and the HDAC inhibitor panobinostat synergistically induced apoptosis of the AML BPCs, but not of normal CD34 þ hematopoietic progenitor cells. This was associated with greater attenuation of c-MYC and BCL2, while increasing p21, BIM, and cleaved PARP levels in the AML BPCs. Cotreatment with JQ1 and panobinostat significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (P < 0.01). These findings highlight cotreatment with a BRD4 antagonist and an HDAC inhibitor as a potentially efficacious therapy of AML. Mol Cancer Ther; 13(5); 1142-54. Ó2014 AACR.

show abstract

Identification of a novel series of BET family bromodomain inhibitors: Binding mode and profile of I-BET151 (GSK1210151A)

Cited by 189 publications

References 8 publications

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib

Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

Contact Info

Product

Resources

About