- GNE-371, a Potent and Selective Chemical Probe for the Second Bromodomains of Human Transcription-Initiation-Factor TFIID Subunit 1 and Transcription-Initiation-Factor TFIID Subunit 1-like
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The biological functions of the dual bromodomains of human transcription-initiation-factor TFIID subunit 1 (TAF1(1,2)) remain unknown, although TAF1 has been identified as a potential target for oncology research. Here, we describe the discovery of a potent and selective in vitro tool compound for TAF1(2), starting from a previously reported lead. A cocrystal structure of lead compound 2 bound to TAF1(2) enabled structure-based design and structure-activity-relationship studies that ultimately led to our in vitro tool compound, 27 (GNE-371). Compound 27 binds TAF1(2) with an IC50 of 10 nM while maintaining excellent selectivity over other bromodomain-family members. Compound 27 is also active in a cellular-TAF1(2) target-engagement assay (IC50 = 38 nM) and exhibits antiproliferative synergy with the BET inhibitor JQ1, suggesting engagement of endogenous TAF1 by 27 and further supporting the use of 27 in mechanistic and target-validation studies.
- Wang, Shumei,Tsui, Vickie,Crawford, Terry D.,Audia, James E.,Burdick, Daniel J.,Beresini, Maureen H.,C?té, Alexandre,Cummings, Richard,Duplessis, Martin,Flynn, E. Megan,Hewitt, Michael C.,Huang, Hon-Ren,Jayaram, Hariharan,Jiang, Ying,Joshi, Shivangi,Murray, Jeremy,Nasveschuk, Christopher G.,Pardo, Eneida,Poy, Florence,Romero, F. Anthony,Tang, Yong,Taylor, Alexander M.,Wang, Jian,Xu, Zhaowu,Zawadzke, Laura E.,Zhu, Xiaoyu,Albrecht, Brian K.,Magnuson, Steven R.,Bellon, Steve,Cochran, Andrea G.
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- SUBSTITUTED PYRROLOPYRDINES AS INHIBITORS OF BROMODOMAIN
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The present invention relates to compounds of formula (I) and to salts thereof, wherein R1, R2, and Q have any of the values defined in the specification, and compositions and uses thereof. The compounds are useful as inhibitors of bromodomains. Also included are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various bromodomain-mediated disorders.
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Page/Page column 111; 112
(2016/06/06)
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- N1-PYRAZOLOSPIROKETONE ACETYL-COA CARBOXYLASE INHIBITORS
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The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt of the compound, wherein R1, R2, R3 and R4 are as described herein; pharmaceutical compositions there-of; and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of an acetyl- CoA carboxylase enzyme(s) in an animal
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Page/Page column 19
(2011/05/16)
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- N2-PYRAZOLOSPIROKETONE ACETYL-COA CARBOXYLASE INHIBITORS
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The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt of said compound, wherein R1, R2, R3 and R4 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of an acetyl- CoA carboxylase enzyme(s) in an animal.
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Page/Page column 39; 40
(2011/06/16)
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