Bifunctional degrader molecules, also called proteolysis-targeting chimeras (PROTACs), are a new modality of chemical tools and potential therapeutics to understand and treat human disease. A required PROTAC component is a ligand binding to an E3 ubiquitin ligase, which is then joined to another ligand binding to a protein to be degraded via the ubiquitin–proteasome system. The advent of nonpeptidic small-molecule E3 ligase ligands revolutionized the field and ushered in the design of drug-like PROTACs with potent and selective degradation activity.
PROTAC (Proteolysis-Targeting Chimeras) is a promising approach in drug discovery that involves the use of small molecules to target specific proteins for degradation by the cellular machinery.
E3 ligase ligand is an important biochemical molecule, which plays an important role in cells. It can bind to E3 ligase, thus promoting protein degradation and cell metabolism. In vivo, the stability and activity of E3 ligase ligands are very important for the normal function of cells. Studies have shown that E3 ligase ligands play an important role in cell cycle, apoptosis, DNA repair and other aspects.
Kymera announced that the first patient has been dosed in the randomized Phase 2 clinical trial in hidradenitis suppurativa (HS) evaluating KT-474 (SAR444656). The Phase 2 study will evaluate the efficacy, safety, pharmacokinetics, and biological effects of KT-474 compared with placebo in adult patients with moderate to severe HS. Kymera's partner Sanofi is conducting the Phase 2 study in HS, and has initiated a second randomized Phase 2 trial in AD. Under the terms of the collaboration, dosing of the first patient in the HS trial generated a milestone payment of $40 million. KT-474 is an oral IRAK4 degrader, in development for the treatment of IL-1R/TLR-driven complex inflammatory diseases where there is an opportunity to significantly advance the standard of care, including HS and AD. Sanofi, which is collaborating with Kymera on the development of KT-474 outside of the oncology and immune-oncology fields, is conducting the Phase 2 studies. Chemenu has been working to develop more compounds for drug discovery. Here are the building blocks we can provide.