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 – Advantages over Conventional Inhibitors
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.
PROTAC Synthesis and Screening Services for Targeted Protein Degradation
- Synthesis of common E3-Ligase ligands (CRBN, VHL, cIAP and MDM-2) and their structural analogues from milligram to gram scale and beyond
- Capability to develop novel flexible or rigid linkers for novel discovery needs
- Experience in the synthesis of molecular glues and monovalent protein degraders
- In-house library of >300 partial PROTACs and linkers for rapid target engagement
- Flexible business models including stand-alone and various integrated services
- Stand-alone biology support including in vitro and in vivo profiling, DMPK, or toxicology
Purification of PROTACs
- Synthetic team with >10 years of experience with PROTAC chemistry to minimize hurdles
- Very experienced analytical team, specifically in purifying PROTACs and Molecular Glues
- Dedicated preparative HPLC systems for supporting PROTAC related projects
- Buchi Lyovapor L-300s for supporting the PROTAC platform in minimizing stability issues
- SFC and HRMS support is provided wherever needed
Integrated Drug Discovery Expertise for PROTACs Screening
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.
- TR-FRET assays for biochemistry (EnVision XCite)
- Cell-based assays for evaluating target degradation (WB, Automated)
- Target binding studies and ternary complex formation (Hi-BiT, Nano-BRET, SPR etc.)
- Preliminary ADME studies (e.g. permeability, solubility, microsomal stability)
- PK studies in rodents (terminal) and in dogs (non-terminal studies)
- Fully integrated and semi-integrated drug discovery programs as well as stand-alone biology services.
Molecular Glues
- Molecular glues are monovalent small molecules (single entities) that reshape the surface of an E3 ligase receptor, assisting novel protein-protein interactions (PPIs) by squeezing between protein–protein interfaces.
- They are much smaller in nature and thus more easily abide by Lipinski’s rule of five, increasing the probability of good oral bioavailability.
- Expected to have better permeability and membrane uptake, more suited for CNS-targets.
| Type | Linker | Mol. Wt. | Lipinski Rule | Binding Pocket | Affinity | |
|---|---|---|---|---|---|---|
| PROTACs | Bivalent | Needed | >700-1000 | No | Needed | Strong |
| 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.
Why Aurigene Pharmaceutical Services?
Ready-to-use partial PROTAC libraries
Flexible business models including mix and match programs
Comprehensive biology support
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Polymorph Screening
ADME/DMPK Services
Drug Formulation Services
In vivo Pharmacology
Medicinal Chemistry
Microbiology Testing
Peptide Synthesis
Development and Kilo Lab
Toxicology Studies
Resources
FEBRUARY 08, 2021
Introduction to PROTAC
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. ...
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Accelerating Drug Discovery Through Innovative Partnerships
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....
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Biologics Manufacturing Services
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. ...
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Expediting early development through innovative precision capsule filling technology
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...
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An efficient and convenient protocol for the synthesis of tetracyclic isoindolo[1,2-a]quinazoline derivatives
2016
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...
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Alternate end-game strategies towards Nirmatrelvir synthesis: Defining a continuous flow process for the preparation of an anti-COVID drug
2005
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 ...
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Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action.
2005
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 ...
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Synthesis of Anti-covid Drug Nirmatrelvir Using Flow Chemistry
2005
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. ...
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Frequently asked questions
What is Target Protein Degradation?
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.
What are the advantages of the Protein degradation approach against conventional approaches?
High target selectivity demonstrates high potencies, less toxic ,and minimizing the risk of developing resistance.
Does PROTAC forms a ternary Complex?
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.
What is Targeted Protein Ubiquitination?
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.
What Is the PROTAC's Cellular Permeability and Target Affinity?
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.
What is the potential of PROTAC for pharmaceutical research?
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.
How are PROTACs gaining traction as a cancer drug discovery technique in the modern era?
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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