GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)
| Autor: | Jane L. Grogan, Ruina Li, Edna F. Choo, Sarah M. Bronner, Maureen Beresini, Jonathan Maher, Patrick Cyr, Yingjie Li, Thomas Hunsaker, Brian K. Albrecht, Colin Masui, Kevin R Clark, Yingqing Ran, Jeremy Murray, Terry Crawford, Xiaorong Liang, Fei Wang, F. Anthony Romero, Xiaocang Wei, Alexander M. Taylor, Georgia Hatzivassiliou, Kyle Clagg, Kwong Wah Lai, Karen E. Gascoigne, Le An, Steven Magnuson, Mark Merchant, John S. Wai, Zhongguo Chen, Jiangpeng Liao, Vickie Tsui, Emily Chan, Kevin X. Chen, Wenfeng Liu, Wei Huang, Dong Yu, Stefan G. Koenig, Susan Kaufman, Xiaoyu Zhu, Gladys de Leon Boenig, Justin Ly, Denise E. de Almeida Nagata, Bing-Yan Zhu |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Pyridines Protein domain Response element Antineoplastic Agents Proto-Oncogene Proteins c-myc Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Dogs Protein Domains In vivo Drug Discovery Structure–activity relationship Animals Humans Cyclic adenosine monophosphate IC50 Chemistry Binding protein Forkhead Transcription Factors CREB-Binding Protein Xenograft Model Antitumor Assays Bromodomain Macaca fascicularis 030104 developmental biology HEK293 Cells Biochemistry Molecular Medicine Pyrazoles RNA Female |
| Zdroj: | Journal of medicinal chemistry. 60(22) |
| ISSN: | 1520-4804 |
| Popis: | Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure–activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC50 = 0.94 nM, BRET IC50 = 6.2 nM; BRD4(1) IC50 = 5100 nΜ) that maintained good in vivo PK properties in multiple species. Compound 19 displays antitumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a dose dependent manner. |
| Databáze: | OpenAIRE |
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