1355554-31-2Relevant academic research and scientific papers
Design, synthesis, and biological activity evaluation of a series of novel sulfonamide derivatives as BRD4 inhibitors against acute myeloid leukemia
Feng, Ziying,Chen, Aiping,Shi, Jing,Zhou, Daoguang,Shi, Wei,Qiu, Qianqian,Liu, Xinhong,Huang, Wenlong,Li, Jieming,Qian, Hai,Zhang, Wenjie
, (2021/07/22)
Accumulating researches have contributed much effect to discover novel chemotherapeutic drug for leukemia with expeditious curative effect, of which bromodomain-containing protein 4 (BRD4) inhibitor is considered as a eutherapeutic drug which has presented efficient cell proliferation suppression effect. In this study, we disclosed a series of phenylisoxazole sulfonamide derivatives as potent BRD4 inhibitors. Especially, compound 58 exhibited robust inhibitory potency toward BRD4-BD1 and BRD4-BD2 with IC50 values of 70 and 140 nM, respectively. In addition, compound 58 significantly suppressed cell proliferation of leukemia cell lines HL-60 and MV4-11 with IC50 values of 1.21 and 0.15 μM. In-depth study of the biological mechanism of compound 58 exerted its tumor suppression effect via down-regulating the level of oncogene c-myc. Moreover, in vivo pharmacokinetics (PK) study was conducted and the results demonstrated better pharmacokinetics features versus (+)-JQ1. In summary, our study discovers that compound 58 represents as a novel BRD4 inhibitor for further investigation in development of leukemia inhibitor with potentiality.
BRD4 protein inhibitor with anti-tumor activity and preparation method and application thereof
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Page/Page column 12, (2019/07/04)
The invention discloses a compound as shown in a formula (I) with anti-tumor activity or pharmaceutically acceptable ester or salt and a preparation method thereof and the application thereof as a BRD4 protein inhibitor. Compared with the prior art, the B
Evaluation of functional groups as acetyl-lysine mimetics for BET bromodomain inhibition
Sharp, Phillip P.,Garnier, Jean-Marc,Huang, David C. S.,Burns, Christopher J.
, p. 1834 - 1842 (2015/01/08)
The ability of various functional groups to engage the acetyl-lysine (KAc) binding site within bromo- and extra-terminal domain (BET) protein family members BRD2, BRD3 and BRD4 was evaluated by screening small molecular fragments-coupled to a known arylsulfonamide scaffold-in biochemical inhibition assays. Useful structure activity relationships have been established and novel functional groups that bind to the KAc binding pocket identified. Additional microsomal degradation studies were also undertaken revealing significant differences in metabolic stability between two commonly employed BET inhibitor fragments.
Fragment-based discovery of bromodomain inhibitors part 2: Optimization of phenylisoxazole sulfonamides
Bamborough, Paul,Diallo, Hawa,Goodacre, Jonathan D.,Gordon, Laurie,Lewis, Antonia,Seal, Jonathan T.,Wilson, David M.,Woodrow, Michael D.,Chung, Chun-Wa
, p. 587 - 596 (2012/03/26)
Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this protein-protein interaction have the potential to modulate multiple diseases as demonstrated by the profound anti-inflammatory and antiproliferative effects of a recently disclosed class of BET compounds. While these compounds were discovered using phenotypic assays, here we present a highly efficient alternative approach to find new chemical templates, exploiting the abundant structural knowledge that exists for this target class. A phenyl dimethyl isoxazole chemotype resulting from a focused fragment screen has been rapidly optimized through structure-based design, leading to a sulfonamide series showing anti-inflammatory activity in cellular assays. This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization.
