Bristol-myers Squibb Compnay

Arvinas Operations, Inc.

Yale University

Arvinas, Inc.

The Scripps Research Institute

Bristol-myers Squibb Holdings Ireland

Lawrence B Snyder

Denis R St Laurent

Fukang Yang

Jeffrey Lee Romine

Makonen Belema

Omar D Lopez

Van N Nguyen

Jason T Goodrich

Nicholas A Meanwell

Andrew Charles Good

Lawrence G Hamann

Rico Lavoie

Edward H Ruediger

David R Langley

Alain Martel

Carol Bachand

Daniel H Deon

Clint A James

Andrew Philip Crew

Jing Wang

Hanqing Dong

Gan Wang

Yimin Qian

Michael Berlin

Michael H Serrano-Wu

Kurt Zimmermann

Yuping Qiu

Keith R Hornberger

Xin Chen

Ramesh Kakarla

Craig M Crews

Xuejie Yang

John F Kadow

John A Bender

Meizhong Jin

Michael Frederick Parker

Kevin W Gillman

Andrew P Degnan

Min Gao

Caterina Ferraro

Julie A Lemm

Hong Huang

Kam Siu

Jayne Kapur

Milind Deshpande

Sanjeev Gangwar

Piyasena Hewawasam

Qian Zhang

Dale L Boger

Min Ding

Scott W Martin

Darren Whitehouse

Zhizhen Barbara Zheng

Ningning Xu

Guo Li

Zhaoxing Meng

John E Leet

Dane M Springer

Wei Zhang

Donald R O'Boyle, Ii

Donald R O'Boyle

Richard Colonno

Dan Sherman

Belema Makonen

Ramesh Kakaria

Donald R Ii O'BOYLE

The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, 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 disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 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. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

Cereblon ligands and bifunctional compounds comprising the same

This disclosure pertains to compounds, the preparation thereof, and the use of these compounds in the treatment of prostate cancer, including metastatic and/or castrate-resistant prostate cancer, in subjects in need thereof.

Compounds and methods for the targeted degradation of androgen receptor

Bifunctional compounds, which find utility as modulators of androgen receptor (AR), are described herein. In particular, the bifunctional compounds of the present disclosure contain on one end a moiety that binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds AR, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

Compounds and methods for the targeted degradation of androgen receptor and associated methods of use

The present disclosure relates to bifunctional compounds, which find utility to degrade (and inhibit) Androgen Receptor. 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 Androgen Receptor such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of Androgen Receptor.

Bifunctional compounds, which find utility as modulators of B-cell lymphoma 6 protein (BCL6; target protein), are described herein. In particular, the bifunctional compounds of the present disclosure contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand that binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

Modulators of BCL6 proteolysis and associated methods of use

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.

Compounds and methods for the enhanced degradation of targeted proteins

The present disclosure relates to bifunctional compounds, which find utility to degrade (and inhibit) Androgen Receptor. In particular, the present disclosure is directed to compounds, which contain on one end a cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds Androgen Receptor, such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present disclosure exhibits a broad range of pharmacological activities associated with compounds according to the present disclosure, consistent with the degradation/inhibition of Androgen Receptor.

The present disclosure relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present disclosure is directed to compounds, which contain on one end a cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds Androgen Receptor, such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present disclosure exhibits a broad range of pharmacological activities associated with compounds according to the present disclosure, consistent with the degradation/inhibition of Androgen Receptor.

The present disclosure relates to bifunctional compounds, which find utility as modulators of enhancer of zeste homolog 2 (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

Compounds and methods for the targeted degradation of enhancer of zeste homolog 2 polypeptide

The disclosure generally relates to compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands, agonists and partial agonists for the mGluR5 receptor and may be useful for the treatment of various disorders of the central nervous system.

Oxazolidinones as modulators of MGLUR5

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Killingworth, CT, United States of America

Lawrence B Snyder