Author: Beresini, Maureen H ; Liao, Jiangpeng ; Zhu, Xiaoyu ; Li, Yingjie ; Romero, F Anthony ; Bronner, Sarah M ; Crawford, Terry D ; Tsui, Vickie ; Zhu, Caicai ; de Leon Boenig, Gladys ; Magnuson, Steven ; Ly, Justin ; Wang, Fei ; Chen, Kevin ; Lai, Kwong Wah ; Liu, Wenfeng ; Murray, Jeremy ; Shen, Weichao ; Chen, Zhongguo ; Kaufman, Susan ; Wai, John ; Choo, Edna F ; Cyr, Patrick

A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35 has excellent CBP potency (CBP IC₅₀ = 1 nM, MYC EC₅₀ = 18 nM), a selectively index of >2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile.

22 Nov 2017·Journal of Medicinal ChemistryQ1 · MEDICINE

GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)

Q1 · MEDICINE

Article

Author: Taylor, Alexander M. ; Albrecht, Brian K. ; Choo, Edna F. ; Masui, Colin ; Romero, F. Anthony ; Murray, Jeremy ; Ly, Justin ; Li, Yingjie ; Lai, Kwong Wah ; Zhu, Bing-Yan ; Cyr, Patrick ; Liu, Wenfeng ; Tsui, Vickie ; Chan, Emily W. ; Huang, Wei ; Crawford, Terry D. ; Chen, Zhongguo ; Clark, Kevin ; Yu, Dong ; Merchant, Mark ; Maher, Jonathan ; Chen, Kevin X. ; Koenig, Stefan G. ; Li, Ruina ; de Almeida Nagata, Denise ; Liao, Jiangpeng ; Bronner, Sarah M. ; Wai, John ; Ran, Yingqing ; Kaufman, Susan ; An, Le ; de Leon Boenig, Gladys ; Magnuson, Steven ; Grogan, Jane L. ; Wei, Xiaocang ; Gascoigne, Karen E. ; Hunsaker, Thomas L. ; Wang, Fei ; Hatzivassiliou, Georgia ; Zhu, Xiaoyu ; Clagg, Kyle ; Beresini, Maureen H. ; Liang, Xiaorong

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.

08 Dec 2016·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300

Q1 · MEDICINE

Article

Author: Choo, Edna F. ; Merchant, Mark ; Poy, Florence ; Wang, Jian ; Spillane, Kerry L. ; Beresini, Maureen H. ; Lai, Kwong Wah ; Wang, Fei ; Bellon, Steven ; Zhu, Xiaoyu ; Murray, Jeremy ; Taylor, Alexander M. ; Tsui, Vickie ; Maher, Jonathan ; Liu, Wenfeng ; Xu, Zhongya ; Kaufman, Susan ; Chan, Emily W. ; Wei, Xiaocang ; Xu, Zhaowu ; Crawford, Terry D. ; Chen, Zhongguo ; Liao, Jiangpeng ; Li, Yingjie ; de Leon Boenig, Gladys ; Chen, Kevin X. ; Conery, Andrew R. ; Magnuson, Steven ; Côté, Alexandre ; Cochran, Andrea G. ; Pardo, Eneida ; Kleinheinz, Tracy ; Cummings, Richard ; Noland, Cameron L. ; Jiang, Ying ; Ly, Justin ; Hunsaker, Thomas L. ; Zawadzke, Laura ; Yen, Ivana ; Kharbanda, Samir ; Gascoigne, Karen E. ; Romero, F. Anthony ; Albrecht, Brian K. ; Jayaram, Hariharan ; Kiefer, James R.

The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC₅₀ = 0.02 μM, BRET IC₅₀ = 0.41 μM, BRD4(1) IC₅₀ = 13 μM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model.

100 Deals associated with GNE-272

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Indication	Highest Phase	Country/Location	Organization	Date
Hematologic Neoplasms	Discovery	US	Constellation Pharmaceuticals, Inc.	28 Sep 2016
Hematologic Neoplasms	Discovery	US	Genentech, Inc.	28 Sep 2016

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