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.

Imide-based modulators of proteolysis and associated methods of use

The invention provides compounds of formula I: or a salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods for treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal using compounds of formula I.

Benzothiazole compounds and their pharmaceutical use

The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional 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. The present application also provides methods for making compounds of the application and intermediates thereof.

Methods to induce targeted protein degradation through bifunctional molecules

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 targeted degradation of bromodomain-containing proteins

Compounds and methods for the enhanced degradation of targeted proteins

Compounds&methods for the enhanced degradation of targeted proteins&other polypeptides by an e3 ubiquitin ligase

Compounds and methods for the enhanced degradation of targeted proteins and other polypeptides by an E3 ubiquitin ligase

La presente invention concerne de nouveaux composes qui trouvent une utilite comme modulateurs, en particulier inhibiteurs de l'ubiquitine ligase VCB E3 et comme agents bioactifs en vue de l'utilisation comme produits therapeutiques pour la stimulation de l'erythropoiese chez un patient ou un sujet, comprenant l'induction de production d'EPO chez le patient ou le sujet, pour le traitement d'anemie et d'ischemie chroniques (limite une lesion cerebrale pendant des episodes d'anemie, ischemie et/ou accident vasculaire cerebral localises et un endommagement au tissu cardiovasculaire pendant une ischemie cardiovasculaire), ainsi que l'amelioration des processus de cicatrisation des plaies. L'invention concerne egalement des compositions pharmaceutiques comprenant des quantites efficaces de composes selon la presente invention individuellement ou en combinaison avec un agent supplementaire stimulant l'erythropoiese, tel que l'EPO, sous la marque Procrit ou Epogene, ou la darbapoietine alpha sous la marque Aranesp. L'invention concerne aussi des procedes de stimulation de l'erythropoiese chez un sujet ou patient, comprenant l'augmentation du nombre de globules rouges et/ou de l'hematocrite du patient, le traitement d'anemie, comprenant l'anemie chronique et l'anemie associee a une maladie renale chronique, la dialyse et la chimiotherapie du cancer, l'ischemie, l'accident vasculaire cerebral et un endommagement au tissu cardiovasculaire pendant une ischemie cardiovasculaire ainsi que l'amelioration des processus de cicatrisation de plaies et la prevention/reduction de cicatrices consecutives a la cicatrisation. La presente invention concerne egalement l'amelioration locale de l'angiogenese par l'induction de VEGF comprenant la cicatrisation des plaies et la reduction d'occlusion d'endoprothese.

Composés et procédés pour l'inhibition de l'ubiquitine ligase vcb e3

La presente invention concerne des composes bifonctionnels, qui sont utiles en tant que modulateurs de l'ubiquitination ciblee, en particulier en tant qu'inhibiteurs d'une variete de polypeptides et d'autres proteines qui sont degradees et/ou autrement inhibees par des composes bifonctionnels selon la presente invention. En particulier, la presente invention concerne des composes qui contiennent a une extremite un ligand VHL qui se lie a l'ubiquitine ligase et a l'autre extremite une fraction qui se lie a une proteine cible de telle sorte que la proteine cible est placee a proximite a l'ubiquitine ligase pour permettre la degradation (et l'inhibition) de cette proteine. La presente invention concerne un large eventail d'activites pharmacologiques associees a des composes selon la presente invention, coherentes avec la degradation/l'inhibition des polypeptides cibles.

Dennis Buckley

Papers

Compounds&methods for the enhanced degradation of targeted proteins&other polypeptides by an e3 ubiquitin ligase

Compounds and methods for the enhanced degradation of targeted proteins and other polypeptides by an E3 ubiquitin ligase

Composés et procédés pour l'inhibition de l'ubiquitine ligase vcb e3

Composés et procédés pour la dégradation améliorée de protéines cibles et d'autres polypeptides par une e3 ubiquitine ligase