New Haven, CT, United States
New Haven, CT, United States

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Patent
Arvinas Inc. and Yale University | Date: 2016-08-05

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.


The description relates to Inhibitors of Apoptosis Proteins (IAPs) 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 invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the IAP 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.


The description relates to imide-based 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 invention. 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.


The present invention 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.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 648.40K | Year: 2016

DESCRIPTION provided by applicant The overall aim of this grant is to generate data to understand and enable the development of a novel therapeutic approach for the treatment of patients with castration resistant prostate cancer Prostate cancer is the third most lethal cancer in the US with new cases and deaths projected to occur in While early detection surgery and hormone deprivation therapies are effective about of localized prostate cancer eventually becomes metastatic castrate resistant prostate cancer mCRPC The major driver of mCRPC is the androgen receptor AR as evidenced by the rise in the circulating levels of the AR target gene prostate specific antigen PSA Patients with these cancers treated with first generation anti androgens flutamide and bicalutamide as well as the second generation anti androgen agents enzalutamide and abiraterone have increased survival but the majority of mCRPCs also develop resistance to these agents Given the central role of AR in prostate cancer agents that target AR with a unique mode of action are urgently needed One approach is to use small molecules to degrade AR We used a novel and innovative approach that employs bi functional small molecules to bind and actively ubiquitinate and degrade AR proteins In preliminary studies these molecules called AR PROTACs have been shown to be potent selective and efficacious in both cell and animals studies A clinical candidate molecule has been chosen to advance towards clinical trials The goals of this grant support that process in several ways they aim to establish the PK PD efficacy relationship for the clinical candidate to demonstrate that this AR PROTAC inhibits the growth of mCRPC tumors that are resistant to current therapy and to conduct Investigational New Drug IND enabling studies on the clinical candidate Taken together these studies will enable a novel agent to move into clinical trials for patients with mCRPC with a good awareness about its manufacture and safety with a clear understanding of how to use this novel therapy and mostly importantly with knowledge of which patients are likely to derive benefit from this new therapy PUBLIC HEALTH RELEVANCE Despite better therapeutic options in the fight against prostate cancer progression to metastatic castration resistant prostate cancer mCRPC remains a leading cause of cancer death among men We have developed a novel therapeutic strategy for the treatment of mCRPC by designing drugs that specifically decrease the levels of the androgen receptor whose activity is linked to disease progression We believe that reducing the levels of this receptor in prostate cancer cells will create a meaningful clinical benefit when compared to blocking the receptorandapos s activity using the currently approved standard of care drugs


The description relates to MDM2 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 invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the MDM2 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.


Patent
Yale University and Arvinas Inc. | Date: 2015-08-10

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.


Patent
Yale University and Arvinas Inc. | Date: 2016-02-17

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.


Patent
Arvinas Inc. and Yale University | Date: 2016-03-18

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.


The description relates to imide-based 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 invention. 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.

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