Proteolysis Targeting Chimera Profacgen

In mammalian cells, protein degradation is mainly carried out by the ubiquitin- proteasome system to dispose of damaged or redundant proteins. Ubiquitin can be attached to the substrate protein through a series of enzymatic reactions leading to the covalent bonding between the C-terminal glycine of ubiquitin and the lysine residue of the substrate. Ubiquitin-tagged proteins are eventually recognized and destructed by proteasome. In spite of the high complexity of ubiquitin system, it is not surprising that some components or processes in this system could provide promising therapeutic intervention for a variety of diseases, including cancer and neurodegenerative diseases. One good example is the E3 ligases, which regulate the attachment of ubiquitin tags to substrate proteins for subsequent degradation.

Illustration of the PROTAC strategyPROTAC

Recently, Arvinas has developed a chemical strategy called Proteolysis Targeting Chimera (PROTAC) for E3 ligase-based degradation of target proteins. 1 In principle, this method can be used to selectively degrade any protein of interest by bringing the target protein into proximity of the E3 ligase for proteasome-mediated proteolysis. Pioneered by Arvinas, PROTAC is becoming an promising strategy to target the so called “undruggable” proteins such as estrogen-related receptor alpha, cellular retinoic acid binding proteins, and BRD4. 2 The key step of PROTAC is the construction a heterobifunctional small molecule that has two warheads – one binds to the target protein, and the other recruits the E3 ligase.

Profacgen, a leading biotech CRO, has been extensively working on bioconjugation services and assay development for more than a decade. Inspired by the discovery of PROTAC, we now offer small molecule- based conjugation services to help our customers develop a new class of therapeutic agents targeting cancers and other difficult-to-treat diseases. This degradation-oriented method is generally more advantageous than traditional enzyme inhibitory strategy in that PROTAC can:

Remove target proteins rather than blocking them; Avoid using high dosage to achieve sufficient inhibition; Reduce toxicity; Degrade “uninhibitable” proteins.

Our services consist of different modules that cover every aspect of PROTAC development, from ligand identification to biological evaluation. Customers are encouraged to choose individual modules that best fit their needs. To achieve the best efficacy, we do recommend our one-stop service package that delivers unrivaled value and will take care of your research project from scratch to full development.

Ligand identification Affinity assays to confirm binding potency, Structural modification, molecular docking.

Chemical conjugation Modification of ligands, linker development, conjugation chemistry, full characterization.

Biological evaluation Enzyme inhibition, protein degradation, in vitro ADME, in vivo tests on animal models.

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