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Compounds & Methods for the Enhanced Degradation of Targeted Proteins & Other Polypeptides by an E3 Ubiquitin Ligase

a technology of ubiquitin ligase and compound, which is applied in the field of bifunctional compounds, can solve the problems of notoriously difficult to target the interaction between proteins and proteins using small molecules, and achieve the effect of improving the efficiency of the target protein and the target protein

Pending Publication Date: 2019-05-02
YALE UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a method for regulating protein activity by using a ubiquitin pathway protein binding moiety and a targeting moiety that recognizes a target protein. This results in the ubiquitin pathway protein binding to the target protein, which can lead to its degradation or inhibition of function. The invention also provides a library of compounds that can be used to screen for target proteins and to treat disease states or conditions through the degradation of the target protein. The technical effects of the invention include the ability to control protein levels and the development of new treatments for disease states or conditions.

Problems solved by technology

Protein-protein interaction interactions are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved.

Method used

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  • Compounds & Methods for the Enhanced Degradation of Targeted Proteins & Other Polypeptides by an E3 Ubiquitin Ligase
  • Compounds & Methods for the Enhanced Degradation of Targeted Proteins & Other Polypeptides by an E3 Ubiquitin Ligase
  • Compounds & Methods for the Enhanced Degradation of Targeted Proteins & Other Polypeptides by an E3 Ubiquitin Ligase

Examples

Experimental program
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Set

[0307]

[0308]VL50 was synthesized from Fmoc-Hyp(OWang)-OAllyl resin (0.156 mmol) according to Solid Phase Synthesis General Method B. It was isolated as a white solid (29.8 mg, 0.084 mmol, 54%). 1H NMR (400 MHz, CD3OD): δ7.34-7.27 (m, 4H); 5.43-5.35 (m, 4H); 3.81-3.78 (dd, J=8 Hz, 4 Hz, 1H); 3.61-3.57 (m, 1H); 2.65-2.61 (m, 2H); 2.57-2.51 (m, 2H); 2.28-2.21 (m, 1H); 2.08-2.02 (m, 1H). 13C NMR (100 MHz, CD3OD): δ 177.53, 174.74, 173.76, 138.75, 133.76, 129.96, 129.49, 70.71, 60.55, 56.47, 43.25, 39.33, 30.97, 30.64. MS (ESI) 354.2 (M+H).

[0309]VL52 was synthesized from Fmoc-Hyp(OWang)-OAllyl resin (0.156 mmol) according to the Solid Phase Synthesis General Method B. It was isolated as a white solid (7.7 mg, 0.021 mmol, 14%). 1H NMR (500 MHz, CD3OD): δ7.41 (d, J=2 Hz, 1H); 7.30 (s, 4H); 6.35-6.34 (dd, J=3 Hz, 2 Hz, 1H); 6.26-6.25 (d, J=3 Hz, 1H); 4.49-4.32 (m, 4H); 3.82-3.73 (m, 3H); 3.65-2.62 (m, 1H); 2.23-2.22 (m, 1H); 2.09-2.06 (m, 1H).13C NMR (125 MHz, CD3OD): δ174.54, 170.58, 14...

examples

(2S,4R)-1-(2-ethoxybenzoyl)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0423]

[0424]A solution of 2-ethoxybenzoic acid (commercially available from for example Aldrich) (29 mg, 0.17 mmol), (2S,4R)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide (50 mg, 0.17 mmol) and DIPEA (0.061 mL, 0.35 mmol) in DMF (1 mL) was treated with HATU (80 mg, 0.21 mmol) and the mixture was stirred at ambient temperature for 2 hours. The product was then subjected to purification by mass-directed automated preparative HPLC (formic acid modifier) to afford the title compound (38 mg, 0.087 mmol, 50% yield). LCMS RT=0.72 min, ES+ve m / z 436 [M+H]+.

[0425]Using a method analogous to that for (2S,4R)-1-(2-ethoxybenzoyl)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide, the following compounds were prepared:

NameStructureYieldRT[M + H]+(2S,4R)-1-benzoyl-4-hydroxy- N-(4-(oxazol-5- yl)benzyl)pyrrolidine-2- carboxamide82%0.65 min392(2S,4R)-4-hydroxy-1-(3- methoxybenzoyl)-N-(4-...

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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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a continuation of, and claims priority to, U.S. patent application Ser. No. 14 / 371,956, filed Jul. 11, 2014, which is a 35 U.S.C. § 371 national phase application of, and claims priority to, PCT Application No. PCT / US2013 / 021136, filed Jan. 11, 2013, which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 61 / 585,769, filed Jan. 12, 2012, all of which applications are incorporated herein by reference in their entireties.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under AI084140 awarded by National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]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 ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D413/14A61K47/64C12N9/00C07D207/16C07D417/12C07D405/12C07D405/06C07D403/06C07D401/10C07D401/06A61K38/05A61K31/422A61K31/427A61K31/437A61K31/4439A61K31/454A61K31/5377A61K38/06A61K45/06C07D413/06C07D417/14C07D471/04C07J43/00C07D207/26C07D413/12A61K47/54
CPCC07D413/14A61K47/545C12N9/93C07D207/16C07D417/12C07D405/12C07D405/06C07D403/06C07D401/10C07D401/06A61K38/05A61K31/422A61K31/427A61K31/437A61K31/4439A61K31/454A61K31/5377A61K38/06A61K45/06C07D413/06C07D417/14C07D471/04C07J43/003C07D207/26C07D413/12A61K47/64A61K47/55A61P1/04A61P11/06A61P15/00A61P17/02A61P21/02A61P25/00A61P25/08A61P25/16A61P25/18A61P25/24A61P25/28A61P29/00A61P3/04A61P31/14A61P31/18A61P35/00A61P35/02A61P37/04A61P43/00A61P7/00A61P7/04A61P9/00A61P9/10A61P9/12A61P3/10A61K31/58C07D403/10C07D413/10C07D417/10G01N33/5008
Inventor CREWS, CRAIG M.BUCKLEY, DENNISCIULLI, ALESSIOJORGENSEN, WILLIAM L.GAREISS, PETER C.VAN MOLLE, INGEGUSTAFSON, JEFFREYTAE, HYUN-SEOPMICHEL, JULIENHOYER, DENTON WADEROTH, ANKE G.HARLING, JOHN DAVIDSMITH, IAN EDWARD DAVIDMIAH, AFJAL HUSSAINCAMPOS, SEBASTIEN ANDRELE, JOELLE
Owner YALE UNIV
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