PROteolysis – TArgeting Chimeras (PROTACs) are a series of hetero-bifunctional molecules that hijack the body’s own natural disposal system to initiate selective degradation of the protein of interest (POI). PROTACs have the potential to overcome most of the limitations of small molecule inhibitors, and they offer several advantages of the traditional concepts of drug discovery. Aurigene offers expertise in the synthesis of PROTACs and partial PROTACs for targeted protein degradation & integrated drug discovery even on the multi-gram scale.
We have extensive experience in not only the synthesis and purification of PROTACs, but also the capability of extensively profiling our synthesized PROTACs including various Biological assays, DMPK and Toxicology support. We are uniquely poised in the Indian CRO market not only as a key player with extensive knowledge in small molecule-based Drug Discovery research, but also can offer our significant experience on the PROTAC-related domain to any potential collaborators.
We are well versed in the synthesis and functionalization of various E3-ligase ligands such as CRBN, VHL, MDM2, and cIAP1 (in multi-gram scale) and in the synthesis of commercially available ligands, as well as in developing novel structural analogues as per custom requests. We also have significant experience in the niche fields of Targeted Protein Degradation (TPD) like molecular glues and ATTECs.
PROTACs have the potential to overcome most of the limitations of small molecule inhibitors, and they offer several advantages of the traditional concepts of drug discovery. This approach also has the potential to target the “undruggable” proteome that limits traditional drugs.
In addition to the Medicinal chemistry of PROTACs, APSL also offer our substantial experience in the Biology of Protein Degraders, gained through the extensive in-house research drug discovery research. We offer comprehensive in-vitro Biology support to interested collaborators, including various biological assays, DMPK and Toxicology support.
|Type||Linker||Mol. Wt.||Lipinski Rule||Binding Pocket||Affinity|
|Molecular Glues||Monovalent||Not Needed||<500||Yes||Not Required||Week|
At Aurigene, we have extensive experience in the synthesis and profiling of molecular glues, which provides us a unique advantage in offering stand alone, semi-integrated and fully integrated discovery programs for our collaborators.
Ready-to-use partial PROTAC libraries
Flexible business models including mix and match programs
Comprehensive biology support
JUNE 28, 2022
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Target Protein degradation is a process in which the protein of interest is degraded using E3 ubiquitin ligase and a chemical linker by polyubiquitination followed by proteasome degradation.
High target selectivity demonstrates high potencies, less toxic ,and minimizing the risk of developing resistance.
A targeting ligand (warhead) for the protein of interest and a ligand that recruits an E3 ubiquitin ligase connected via a carefully-chosen chemical linker (PROTAC). The resulting compound can induce formation of a ternary complex (the target, degradation compound and E3 ligase). The design of degrader compounds is critical to form an effective ternary complex.
The addition of ubiquitin to a substrate protein is called ubiquitination. Ubiquitination of target proteins involves a three-step enzymatic process, i.e., Activation, conjugation, and Ligation. Finally, polyubiquitinated proteins are recognized by the proteasome then degrades into small peptides by proteolysis.
Cellular Permeability and Target Affinity are the important factors to decide the effective binding of PROTAC with target protein and ubiquitination. These parameters play a crucial role in the designing of PROTAC molecules.
PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance of affecting nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. It has attracted great attention both from academia and industry.
Catalytic in nature, targeted degradation and selectivity provide a niche for PROTAC applications in cancer diseases and immune disorders, viral infections, and neurodegenerative diseases.
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