Biased Multicomponent Reactions to Develop Novel Bromodomain Inhibitors

McKeown, M.; Shaw, Daniel L.; Fu, Harry; Liu, Shuai; Xu, Xiang; Marineau, Jason; Huang, Yibo; Zhang, Xiaofeng; Buckley, Dennis L.; Kadam, Asha; Zhang, Zijuan; Blacklow, Stephen C.; Qi, Jun; Zhang, Wei; Bradner, James E.

doi:10.1021/jm501120z

Cited by 87 publications

(92 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1a). To assess competitive binding with JQ1 to the BET bromodomains, we adapted a luminescence homogeneous, nanomaterial-based proximity assay (AlphaScreen™) for BD1 of BRD4 (hereafter referred to as BRD4(1)) as the primary screening method 22,23 . In this assay system, the active ( S )-enantiomer of JQ1 exhibited an IC 50 of 21 nM (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Design and characterization of bivalent BET inhibitors

et al. 2016

Self Cite

View full text Add to dashboard Cite

Cellular signaling is often propagated by multivalent interactions. Multivalency creates avidity, allowing stable biophysical recognition. Multivalency is an attractive strategy for achieving potent binding to protein targets, as the affinity of bivalent ligands is often greater than the sum of monovalent affinities. The BET family of transcriptional coactivators features tandem bromodomains, through which BET proteins naturally bind acetylated histones and transcription factors. All reported BRD4 antagonists bind in a monovalent fashion. Here, we report the first bivalent BET bromodomain inhibitor, MT1 that has unprecedented potency. Biophysical and biochemical studies suggest MT1 is an intramolecular bivalent BRD4 binder that is over 100-fold more potent in cellular assays compared to the corresponding monovalent antagonist, JQ1. MT1 significantly delayed leukemia progression in mice (Mus musculus) compared to JQ1. These data qualify a powerful chemical probe for BET bromodomains and extensible rationale for further development of multidomain epigenetic reader protein inhibitors.

show abstract

Section: Resultsmentioning

confidence: 99%

Design and characterization of bivalent BET inhibitors

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…18 The potency of their most potent compound via isothermal titration calorimetry for Brd4 is 0.55 μM at 15 °C. Compound 3 compares favorably to the most potent compound from McKeown and colleagues in overall yield (70% vs. 45%) and number of synthetic steps (1 vs. 2), and compound 3s shows improvements in potency over compound 3 .…”

Section: Discussionmentioning

confidence: 99%

“…2,13–17 The most accessible inhibitor reported to date was synthesized in two steps, the first of which was a multicomponent reaction, highlighting the demand for rapid, facile syntheses. 18 …”

Section: Introductionmentioning

confidence: 99%

BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen

et al. 2017

Self Cite

View full text Add to dashboard Cite

Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. 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. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure-activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development.

show abstract

“…Past and recent development of BET bromodomain inhibitors has been focused on either increasing the affinity, specificity, and efficacy of current compounds, or on the development of new chemical families of inhibitors. Current approaches include optimizing BET bromodomain inhibitors based on the imidazo[1,2-a]pyrazine scaffold shared by both I-BET and JQ1, and synthesizing novel bromodomain inhibitors with dissociation constants in the nanomolar range [152, 153]. Efforts to develop novel BET inhibitors resulted in the development of the isoxazole azepine, the benzo[cd]indol-2(1H)-one, and the 5- and 6-isoxazolyl benzimidazole family of small molecules as “selective” inhibitors of the BET proteins [154–156], OTX015, and the Benzoisoxazoloazepine inhibitor (CPI-0610) [144].…”

Section: Bet Inhibitors and Clinical Applications For Inflammationmentioning

confidence: 99%

BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer

Nicholas

Andrieu

Strissel

et al. 2016

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Chronic inflammation drives pathologies associated with type 2 diabetes (T2D) and breast cancer. Obesity-driven inflammation may explain increased risk and mortality of breast cancer with T2D reported in the epidemiology literature. Therapeutic approaches to target inflammation in both T2D and cancer have so far fallen short of the expected improvements in disease pathogenesis or outcomes. The targeting of epigenetic regulators of cytokine transcription and cytokine signaling offers one promising, untapped approach to treating diseases driven by inflammation. Recent work has deeply implicated the Bromodomain and Extra-Terminal domain (BET) proteins, which are acetylated histone “readers”, in epigenetic regulation of inflammation. This review focuses on inflammation associated with T2D and breast cancer, and the possibility of targeting BET proteins as an approach to regulating inflammation in the clinic. Understanding inflammation in the context of BET protein regulation may provide a basis for designing promising therapeutics for T2D and breast cancer.

show abstract

Biased Multicomponent Reactions to Develop Novel Bromodomain Inhibitors

Cited by 87 publications

References 50 publications

Design and characterization of bivalent BET inhibitors

Design and characterization of bivalent BET inhibitors

BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen

BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer

Contact Info

Product

Resources

About