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End-to-End expertise in PROTAC: Early proof-of-concept to formulation and manufacturing

PROteolysis Targeting Chimeras (PROTACs) have garnered a lot of attention in recent times for their ability to exploit the cell’s own degradation machinery (ubiquitin-proteasome system) to irreversibly degrade target proteins. However, the design and optimization of PROTAC molecules pose a number of challenges.

Common challenges in PROTAC programs

At Syngene, we have end-to-end expertise in PROTACs from Target identification to clinical and commercial manufacturing. With 450+ dedicated TPD scientists and more than 15 global clients, we have a strong track record in accelerating PROTAC programs for our clients. Our Discovery team has successfully identified Hits and leads across several projects, including programs moving into preclinical development through a strong collaborative effort.

Syngene’s end-to-end PROTAC toolbox

With expertise encompassing discovery, development, and manufacturing, our scientists ensure the seamless progression of PROTAC molecules from idea to market. Currently, we are expanding our capabilities to support programs based on molecular glues, ribonuclease targeting chimeras (RIBOTACs), and lysosome-targeting chimeras (LYTACs), termed as X-TACs.

Our end-to-end PROTAC solutions

We can help you evaluate targets to determine whether they are amenable to degradation using the following approaches:

  1. WES/ICW for estimating target expression and its kinetics in the cell line/s of interest

We provide a quantitative estimation of the target expression kinetics – a crucial first step in the PROTAC strategy for TPD — to determine endogenous degradation of the target of interest.

For advanced studies supporting the regular screening of compounds at higher throughputs, we perform target degradation assays using HiBiT or Nano-Luc tag-based approaches.

  1. dTAG approach
    To evaluate the suitability of the target, we use a generalized tag-based strategy called degradation TAG (dTAG system). The system evaluates the effects of rapid and selective degradation of protein targets in time scales not possible with traditional genetic approaches.

We provide high-quality in vitro assay data with a quick turnaround time enabling you to make informed decisions for SAR and medicinal chemistry-related iterations to advance your R&D programs.

Our assay biology group has expertise in selecting the right assay using the right platforms and approaches based on the target and E3 ligase to enable quick identification of Hits. We evaluate the compounds for their biochemical and cell-based assay potencies for in vitro ranking. This is followed by DMPK (solubility, permeability, stability, mouse/rat PK) and in vivo studies for PROTAC screening as per the screening cascade.


• Finding suitable E3 ligand
• Linker length optimization
• Exit vector optimization
• Optimization of physicochemicalproperties
• Purification of final degraders


• Binding affinity
• Ternary complex formation
• Assay development for target
engagement and target degradation
• Data correlation- cooperativity vs. degradation vs. potency


• Solubility
• Permeability/influx
• Tight binding to proteins
• Appropriate formulation strategy early in the program
• PD outlasts PK

Syngene’s portfolio for PROTAC assays.

Syngene offers all services in the drug discovery pipeline to advance your idea for lead degrader identification and optimization. The services include –

  • ADME Assays- Solubility, permeability, stability
  • PK- rodents- (mice & rats) and non rodents
  • MetID- Linker cleavage & other metabolites
  • Chemical synthesis & series optimization
  • Suitable E3 ligase ligand & Linker length optimization
  • Exit vector optimization
  • In vitro safety: hERG
  • Ion Channels
  • AMES/Genotox

Syngene’s safety team has the right expertise to assess the safety of the molecule using rodent models and in vitro assays. Our scientists also have many years of experience in IND filing to help you overcome any challenges you many face during the process. Our IND-enabling services are as follows:

  • DRF Tox (R/NR)
  • Bioanalysis
  • GLP tox (R/NR)
  • GLP bioanalysis
  • SEND services

Syngene offers many Formulation approaches to ensure the bioavailability of your PROTAC compounds. Our Formulation approaches for improving poor permeability and poor solubility issues are as follows:

  • Polymer formulations: Conventional tablets/capsules with drug or granules filled into bottles and capsules, micellar systems based on surfactants or phospholipids, hydrogels, microparticles, microspheres, lipid nanoparticles, microemulsions, and self-micro emulsifying drug delivery systems (SMEDDS)
  • Particle size reduction using micronization  and nanosuspensions
  • Solid dispersions using spray drying

Our formulation work plan is as follows:

Syngene’s Formulation work plan

Customer speak

We value our strong relationship with Syngene to support C4 Therapeutics’ research efforts across chemistry and biology to advance targeted protein degradation science. The scientific discussions, flexibility, and transparency between the teams have been key to making our collaboration successful.
Chris Nasveschuk
Senior Vice President, Chemistry, C4 Therapeutics

Other videos

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Targeted Protein Degradation: A novel therapeutic modality
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Reinventing ADME PK Profiling Strategy for PROTACs discovery

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