To develop an ideal PROTAC^® molecule with huge potential to treat diseases, the specificity and affinity of ligands for target disease-causing proteins are very important. Empowered by our experienced scientists and advanced drug discovery platform, Creative Biolabs is fully competent and dedicated to providing various ligands for target proteins of interest or ligand design service to meet the drug discovery goals of our clients.

Background

A wide range of therapeutic targets has been identified in the human proteome for malignant tumors and other diseases. While a majority of these targets can't be curative by current existing small molecules that inhibit the functions of these proteins. Herein, a novel therapeutic approach to target these “undruggable” proteins is inevitable. In the meantime, high drug dosages and continuous exposure to small molecule inhibitors may inadvertently result in off-target effects. To target a wider range of proteins with high specificity and affinity, PROTAC^® is emerging as a promising technique in the development of therapeutics. For PROTAC^® design and development, identifying a specific ligand is very important to determine the specificity of the PROTAC^® molecule.

Introduction of Ligand Design for Target Protein

With huge advantages, PROTAC^® can be broadly applicable to a variety of target classes (see Fig.1). In addition, PROTAC^® is capable of offering greater degradation selectivity compared with binding selectivity derived from the target ligand used, this means even the ligand candidate is weak binding to the target protein, it still can drive robust degradation. Creative Biolabs is committed to providing the following services including but not limited to:

• Our service covers all aspects of target proteins: cytosolic, nuclear and trans-membrane targets.
• If the target proteins of interest are reported transcription factors, non-enzymatic proteins, scaffold proteins, kinases, receptors or bromodomains, we yield ligand products to you based on current researches, and we also offer ligand design service to fit your needs. In addition, we offer synthesis services to get an efficient ligand for you.
• For the target proteins with little references, our superior team is committed to providing the ligand design service to ensure an efficient PROTAC^® molecule.
• We allow the rapid affinity identification of ligand candidates for target proteins.
• Structural modification to optimize the ligand to improve the poor stability, biodistribution, and penetrability in vivo is also achievable at Creative Biolabs.

Fig.1 Selected bifunctional molecules hijacking the VHL E3 ligase to degrade various target proteins. (Collins, 2017)

Here is a simple list of ideal targets for PROTAC^® technology for your reference.

• Targeting nuclear receptors (e.g. AR, ER, RAR)
• Targeting protein kinases (e.g. Akt, BCR, c-Abl, BTK, ALK, CDK9, RIPK2, DAPK1, PSD-95)
• Targeting transcriptional regulatory proteins (e.g. BRD4, Sirt2, HDAC6, TRIM24, IKZF1/3, Smad3)
• Targeting regulatory proteins (e.g. CRABP-I/II, TACC3, AHR, FKBP12, ERRα, X-protein)
• Targeting neurodegenerative related proteins (e.g. Huntingtin, Tau, α-synuclein)
• Targeting cellular metabolic enzymes (e.g. MetAP-2, DHODH)

Fig.2 PROTAC^®-mediated protein degradation.

Highlight Features of Our Services

• Ligand design for various forms like small molecules, peptides, and antibodies, etc.
• Experienced scientists and technicians
• Cutting-edge consulting service
• One-stop drug discovery service
• Superior after-sale service

As a leader in therapeutic small molecule discovery and development, Creative Biolabs is dedicated to exploring novel small molecules to promote the field of drug discovery. Using the advanced ligand design platform, we are confident in presenting a comprehensive set of services to develop an ideal PROTAC^® for worldwide clients. Please feel free to contact us with any questions.

Reference

1. Collins, I.; et al. Chemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway. Biochem J. 2017, 474(7): 1127-1147.