WO2013106643 COMPOUNDS & METHODS FOR THE ENHANCED DEGRADATION OF TARGETED PROTEINS & OTHER POLYPEPTIDES BY AN E3 UBIQUITIN LIGASE

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Publication Number WO/2013/106643

Publication Date 18.07.2013

International Application No. PCT/US2013/021136

International Filing Date 11.01.2013

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Applicants

YALE UNIVERSITY [US]/[US]
GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT LIMITED [GB]/[GB]
CAMBRIDGE ENTERPRISE LIMITED UNIVERSITY OF CAMBRIDGE [GB]/[GB]

Inventors

CREWS, Craig, M.
BUCKLEY, Dennis
CIULLI, Alessio
JORGENSEN, William
GAREISS, Peter, C.
MOLLE, Inge, Van
GUSTAFSON, Jeffrey
TAE, Hyun-Seop
MICHEL, Julien
HOYER, Dentin, Wade
ROTH, Anke, G.
HARLING, John, David
SMITH, Ian Edward, David
MIAH, Afjal, Hussain
CAMPOS, Sebastien, Andre
LE, Joelle

Agents

COLEMAN, Henry, D.

Priority Data

61/585,769

12.01.2012

Publication Language English (en)

Filing Language English (EN)

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Title

(EN) COMPOUNDS & METHODS FOR THE ENHANCED DEGRADATION OF TARGETED PROTEINS & OTHER POLYPEPTIDES BY AN E3 UBIQUITIN LIGASE

(FR) COMPOSÉS ET PROCÉDÉS POUR LA DÉGRADATION AMÉLIORÉE DE PROTÉINES CIBLES ET D'AUTRES POLYPEPTIDES PAR UNE E3 UBIQUITINE LIGASE

Abstract

(EN) 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.

(FR) La présente invention concerne des composés bifonctionnels, qui sont utiles en tant que modulateurs de l'ubiquitination ciblée, en particulier en tant qu'inhibiteurs d'une variété de polypeptides et d'autres protéines qui sont dégradées et/ou autrement inhibées par des composés bifonctionnels selon la présente invention. En particulier, la présente invention concerne des composés qui contiennent à une extrémité un ligand VHL qui se lie à l'ubiquitine ligase et à l'autre extrémité une fraction qui se lie à une protéine cible de telle sorte que la protéine cible est placée à proximité à l'ubiquitine ligase pour permettre la dégradation (et l'inhibition) de cette protéine. La présente invention concerne un large éventail d'activités pharmacologiques associées à des composés selon la présente invention, cohérentes avec la dégradation/l'inhibition des polypeptides ciblés.

C	CHEMISTRY; METALLURGY
07	ORGANIC CHEMISTRY
K	PEPTIDES
19	Hybrid peptides

C	CHEMISTRY; METALLURGY
07	ORGANIC CHEMISTRY
D	HETEROCYCLIC COMPOUNDS
413	Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
02	containing two hetero rings
12	linked by a chain containing hetero atoms as chain links

C	CHEMISTRY; METALLURGY
07	ORGANIC CHEMISTRY
D	HETEROCYCLIC COMPOUNDS
413	Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
14	containing three or more hetero rings

C	CHEMISTRY; METALLURGY
07	ORGANIC CHEMISTRY
D	HETEROCYCLIC COMPOUNDS
207	Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
02	with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
18	having one double bond between ring members or between a ring member and a non-ring member
22	with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
24	Oxygen or sulfur atoms
26	2-Pyrrolidones

C	CHEMISTRY; METALLURGY
07	ORGANIC CHEMISTRY
J	STEROIDS
9	Normal steroids containing carbon, hydrogen, halogen, or oxygen, substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

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1. WO2013106643 - COMPOUNDS & METHODS FOR THE ENHANCED DEGRADATION OF TARGETED PROTEINS & OTHER POLYPEPTIDES BY AN E3 UBIQUITIN LIGASE

A	HUMAN NECESSITIES
61	MEDICAL OR VETERINARY SCIENCE; HYGIENE
K	PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31	Medicinal preparations containing organic active ingredients
33	Heterocyclic compounds
395	having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
41	having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
42	Oxazoles
422	not condensed and containing further heterocyclic rings

A	HUMAN NECESSITIES
61	MEDICAL OR VETERINARY SCIENCE; HYGIENE
P	SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
1	Drugs for disorders of the alimentary tract or the digestive system
04	for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

C	CHEMISTRY; METALLURGY
12	BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
N	MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
9	Enzymes; Proenzymes; Compositions thereof
93	Ligases (6)

A	HUMAN NECESSITIES
61	MEDICAL OR VETERINARY SCIENCE; HYGIENE
K	PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47	Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50	the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51	the non-active ingredient being a modifying agent
54	the modifying agent being an organic compound
55	the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds

A	HUMAN NECESSITIES
61	MEDICAL OR VETERINARY SCIENCE; HYGIENE
K	PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47	Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50	the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51	the non-active ingredient being a modifying agent
54	the modifying agent being an organic compound
554	the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid

A	HUMAN NECESSITIES
61	MEDICAL OR VETERINARY SCIENCE; HYGIENE
K	PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47	Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50	the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51	the non-active ingredient being a modifying agent
62	the modifying agent being a protein, peptide or polyamino acid
64	Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent