Patent
Compounds&methods for the enhanced degradation of targeted proteins&other polypeptides by an e3 ubiquitin ligase
Craig M. Crews,Dennis Buckley,Alessio Ciulli,William L. Jorgensen,Peter C. Gareiss,Inge Van Molle,Jeffrey L. Gustafson,Hyun-Seop Tae,Julien Michel,Dentin Wade Hoyer,Anke G. Roth,John D. Harling,Ian Edward David Smith,Afjal Hussain Miah,Sebastien Andre Campos,Joelle Le +15 more
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TLDR
In this paper, a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides, are described.Abstract:
The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.read more
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Imide-based modulators of proteolysis and associated methods of use
Craig M. Crews,Andrew P. Crew,Hanqing Dong,Jing Wang,Yimin Qian,Kam W. Siu,Caterina Ferraro,Meizhong Jin,Xin Chen +8 more
TL;DR: In this article, the authors describe imide-based compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides.
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Methods to induce targeted protein degradation through bifunctional molecules
TL;DR: In this article, bifunctional compounds which act as protein degradation inducing moieties are presented. But the present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctionsal compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders.
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Compounds and methods for the targeted degradation of bromodomain-containing proteins
TL;DR: In this paper, a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides, are described.
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Compounds and methods for the enhanced degradation of targeted proteins
Andrew P. Crew,Craig M. Crews,Chen Xin,Hanqing Dong,Caterina Ferraro,Yimin Qian,Kam W. Siu,Wang Jing,Meizhong Jin,Michael Berlin,Kurt Zimmerman,Lawrence Snyder +11 more
TL;DR: In this paper, a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides, are described.
References
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Journal ArticleDOI
Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL.
Wai-Ching Hon,Michael I. Wilson,Karl Harlos,Timothy D. W. Claridge,Christopher J. Schofield,Christopher W. Pugh,Patrick H. Maxwell,Peter J. Ratcliffe,David I. Stuart,E. Yvonne Jones +9 more
TL;DR: Optimize hydrogen bonding to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues in two functionally independent regions of HIF-1α, providing a new focus for development of therapeutic agents to modulate cellular responses to hypoxia.
Journal ArticleDOI
Small‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α
Dennis L. Buckley,Jeffrey L. Gustafson,Inge Van Molle,Anke G. Roth,Hyun Seop Tae,Peter C. Gareiss,William L. Jorgensen,Alessio Ciulli,Craig M. Crews +8 more
TL;DR: Novel small-molecule inhibitors of the interaction between VHL and its molecular target HIF1α, a transcription factor involved in oxygen sensing are reported.
Journal ArticleDOI
Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase.
Mariam Aghajan,Nao Jonai,Karin Flick,Fei Fu,Manlin Luo,Xiaolu Cai,Ikram Ouni,Nathan W. Pierce,Xiaobo Tang,Brett Lomenick,Robert Damoiseaux,Rui Hao,Pierre-Marie Del Moral,Rati Verma,Ying Li,Cheng Li,Kendall N. Houk,Michael E. Jung,Ning Zheng,Lan Huang,Raymond J. Deshaies,Peter K. Kaiser,Jing Huang +22 more
TL;DR: It is demonstrated that SMER3 diminishes binding of the F-box subunit Met30 to the SCF core complex in vivo and in vitro, and there is no fundamental barrier to obtaining specific inhibitors to modulate function of individual SCF complexes.
Patent
Ubiquitin ligase inhibitors
Rajinder Singh,Usha V. Ramesh,Sarkiz D. Issakani,Jianing Huang,Taisei Kinoshita,Tarikere L. Gururaja +5 more
TL;DR: In this paper, the authors describe compounds useful as ubiquitin ligase inhibitors, which are useful as inhibitors of the biochemical pathways of organisms in which ubiquitination is involved.
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Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs.
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