1445993-86-1Relevant academic research and scientific papers
Discovery of Dual TAF1-ATR Inhibitors and Ligand-Induced Structural Changes of the TAF1 Tandem Bromodomain
Bikowitz, Melissa J.,Chen, Jiandong,Chen, Lihong,Grassie, Dylan,Karim, Rezaul Md,Lopchuk, Justin M.,Lu, Junhao,Sch?nbrunn, Ernst,Shultz, Zachary P.,Yang, Leixiang
, p. 4182 - 4200 (2022/03/14)
Bromodomains regulate chromatin remodeling and gene transcription through recognition of acetylated lysines on histones and other proteins. Bromodomain-containing protein TAF1, a subunit of general transcription factor TFIID, initiates preinitiation complex formation and cellular transcription. TAF1 serves as a cofactor for certain oncogenic transcription factors and is implicated in regulating the p53 tumor suppressor. Therefore, TAF1 is a potential target to develop small molecule therapeutics for diseases arising from dysregulated transcription, such as cancer. Here, we report the ATR kinase inhibitor AZD6738 (Ceralasertib) and analogues thereof as bona fide inhibitors of TAF1. Crystallographic and small-angle X-ray scattering studies established that newly identified and previously reported inhibitors stabilize distinct structural states of the TAF1 tandem bromodomain through “open-closed” transitions and dimerization. Combined with functional studies on p53 signaling in cancer cell lines, the data provide new insights into the feasibility and challenges of TAF1 inhibitors as chemical probes and therapeutics.
BRD4 inhibitor as well as a preparative method and use thereof
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Paragraph 0059; 0060; 0067; 0068, (2021/05/21)
The compound of formula (I) has a good inhibitory effect on the proliferation of human prostate cancer cells CWR22RV1 and breast cancer cells; and combined use of the compound with an androgen receptor inhibitor HC-1119 significantly enhances the inhibitory effect on prostate cancer cells, and the inhibitory effect increases with increased concentration. The compound of formula (I) can not only be used independently to prepare an antineoplastic agent but can also be used in combination with other agents having antineoplastic effects, such as an androgen receptor inhibitor, or other targeting drugs etc., to prepare an antineoplastic agent having stronger therapeutic effects, especially an agent for treating prostate cancer and breast cancer.
Compound with BRD4 inhibitory activity, preparation method and application thereof
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Paragraph 0452-0453; 0463-0465, (2021/04/10)
The invention discloses a compound with BRD4 inhibitory activity, a preparation method and application thereof. The structure of the compound with the BRD4 inhibitory activity is shown as a formula I, and definitions of substituent groups are shown in the specification and claims. The compound provided by the invention has very high bromodomain protein inhibition activity, especially BRD4 targeted inhibition activity, and can be used for treating or/and preventing related diseases mediated by bromodomain protein.
Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity
Pillow, Thomas H.,Adhikari, Pragya,Blake, Robert A.,Chen, Jinhua,Del Rosario, Geoffrey,Deshmukh, Gauri,Figueroa, Isabel,Gascoigne, Karen E.,Kamath, Amrita V.,Kaufman, Susan,Kleinheinz, Tracy,Kozak, Katherine R.,Latifi, Brandon,Leipold, Douglas D.,Sing Li, Chun,Li, Ruina,Mulvihill, Melinda M.,O'Donohue, Aimee,Rowntree, Rebecca K.,Sadowsky, Jack D.,Wai, John,Wang, Xinxin,Wu, Cong,Xu, Zijin,Yao, Hui,Yu, Shang-Fan,Zhang, Donglu,Zang, Richard,Zhang, Hongyan,Zhou, Hao,Zhu, Xiaoyu,Dragovich, Peter S.
, p. 17 - 25 (2019/11/20)
The ability to selectively degrade proteins with bifunctional small molecules has the potential to fundamentally alter therapy in a variety of diseases. However, the relatively large size of these chimeric molecules often results in challenging physico-chemical properties (e. g., low aqueous solubility) and poor pharmacokinetics which may complicate their in vivo applications. We recently discovered an exquisitely potent chimeric BET degrader (GNE-987) which exhibited picomolar cell potencies but also demonstrated low in vivo exposures. In an effort to improve the pharmacokinetic properties of this molecule, we discovered the first degrader-antibody conjugate by attaching GNE-987 to an anti-CLL1 antibody via a novel linker. A single IV dose of the conjugate afforded sustained in vivo exposures that resulted in antigen-specific tumor regressions. Enhancement of a chimeric protein degrader with poor in vivo properties through antibody conjugation thereby expands the utility of directed protein degradation as both a biological tool and a therapeutic possibility.
COMPOUND FUNCTIONING AS BROMODOMAIN PROTEIN INHIBITOR, AND COMPOSITION
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, (2020/11/22)
The invention relates to a bromodomain inhibitor. The invention also provides compositions and formulations comprising such compounds, and methods of using and preparing such compounds.
BET INHIBITORS FOR MODULATING DUX4 EXPRESSION IN FSHD
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, (2020/07/14)
The present disclosure provides BET inhibitors of the formula: wherein the variables are defined herein, as well as pharmaceutical compositions thereof. The present disclosure also provides methods of treating a patient comprising administering a bromo- and extra-terminal (BET) domain inhibitor for the treatment of FSHD which modulates DUX4 expression. In some embodiments, the present methods comprise using one or more BET inhibitors as a therapeutic agent for the treatment of FSHD patients including patients who are being treated with one or more palliative treatments such as therapy and/or agents which lead to increased muscle mass.
TERT-BUTYL (S)-2-(4-(PHENYL)-6H-THIENO[3,2-F][1,2,4]TRIAZOLO[4,3-A] [1,4]DIAZEPIN-6-YL) ACETATE DERIVATIVES AND RELATED COMPOUNDS AS BROMODOMAIN BRD4 INHIBITORS FOR TREATING CANCER
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Paragraph 0344, (2020/05/06)
The present disclosure relates to te rt-butyl (S)-2-(4-(phenyl)-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a] [l,4]diazepin-6-yl) acetate derivatives and related compounds as bromodomain BRD4 inhibitors for treating cancer. Exemplary compounds are e.g. tert-butyl (S)-2-(4-(4-(3-aminoprop-l-yn-l-yl)phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetate (example 1, compound la), tert-butyl(S,E)-2-(4-(4-(3-aminoprop-l-en-l-yl)phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetate (example 6, compound 6a) or tert-butyl(S)-2-(4-(4-(3-(hydroxyamino)prop-l-yn-l-yl)phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a] [l,4]diazepin-6-yl)acetate (example 8, compound 8a).Results of biological assays, such as e.g. BRD4 BD1 and BD2 binding (table 2), cell proliferation assays (table 6) and inhibition of MYC expression in MV-4-11 cells (table 7) are disclosed.
COMPOUNDS COMPRISING N-METHYL-2-PYRIDONE, AND PHARMACEUTICALLY ACCEPTABLE SALTS
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Page/Page column 49, (2020/12/30)
The present invention concerns compounds comprising N-methyl-2-pyridone, and pharmaceutically-acceptable salts and compositions of such compounds. Such compounds are useful in anti-inflammatory and anti-cancer therapies. Therefore, the present invention also concerns such compounds for use as medicaments, particularly for the treatment of inflammatory diseases and oncology.
(4-HYDROXYPYRROLIDIN-2-YL)-HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF
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, (2019/05/15)
The present disclosure relates to bifunctional compounds of formula (I), which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds which contain on one end a VHL ligand moiety, which binds to the VHL E3 ubiquitin ligase, and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. Also disclosed are VHL ligands of formula (III).
BET protein inhibitor and preparation method and application thereof
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, (2019/07/29)
The invention belongs to the technical field of biological medicine, and particularly relates to a BET protein inhibitor and a preparation method and application thereof. Compared with the prior art,structural improvement is further conducted on the basis
