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
FEBRUARY 08, 2021
PROteolysis TArgeting Chimeras (PROTAC) are a series of hetero-bifunctional molecules that hijack the body’s natural disposal system to initiate selective degradation of the protein of interest (POI). They are generally bifunctional molecules that hijack the Ubiquitin Proteasome System (UPS) to achieve the total degradation of a disease-related target protein. ...Read More
Genomics plays a vital role in identifying which gene is associated with a specific disease. A gene called CNOT1 is for example known for it's effect on brain development and for impairing memory and learning. Despite the great promise genomics provides in understanding the disease, genes are not the best drug targets....Read More
Our manufacturing services cater to both GMP and non-GMP manufacturing for pre-clinical development as well as GMP operation to support clinical or commercial needs for any recombinant proteins expressed in suspension mammalian culture or E. coli. ...Read More
Introduction: Any new chemical entity (NCE) needs to undergo various stages of development such as preclinical and clinical trials before drug product is approved by regulatory agencies and available for patient. Formulations developed during early phases are simple formulations to enable phase appropriate studies like screening, dose ranging, toxicological and d...Read More
A convenient and one-pot synthesis of tetracyclic isoindolo [1,2-a]quinazoline derivatives via Lewis acid mediated sequential C–N bond formation reactions is reported. This protocol provides a simple and rapid strategy for the synthesis of 12-benzylidene-10,12-dihydroisoindolo[1,2-b]quinazoline derivatives. However, a variety of tetracyclo indole fused quinazol...Read More
Scalable alternate end-game strategies for the synthesis of the anti-COVID drug molecule Nirmatrelvir (1,PF-07321332) have been described. The first involves a direct synthesis of 1 via amidation of the carboxylic acid 7 (suitably activated as a mixed anhydride with either pivaloyl chloride or T3P) with the ...Read More
Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of a novel ATP-competitive MEK1/2 inhibitor with efficacy in wildtype (WT) and mutant MEK12 models. Starting from a HTS hit, we obtained selective, cellularly active ...Read More
Synthesis of the anti-covid therapeutic Nirmatrelvir by using flow chemistry to enhance efficiency of amide to nitrile conversion in a functionally and Stereochemically Embellished environment. ...Read More
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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