Ligand Design for Smad3-targeting PROTAC^®

With years' extensive experience and advanced proteolysis-targeting chimera (PROTAC^®) development platform, Creative Biolabs becomes one of the well-recognized professionals in high-quality ligand design and preparation. Our scientists are dedicated to designing the best-fit ligands for your Smad3-targeting PROTAC^® project and preparing them in a high-quality manner.

Introduction of Smad3

The SMAD family of proteins is a group of intracellular signal transducer proteins. Smad3 is an essential transport protein in the transforming growth factor-beta (TGF-β) signaling pathway. Smad3 is responsible for the direct transfer of the TGF-β signals from the cell surface to the nucleus and the regulation of the expression of targets, and cell proliferation. It has been confirmed that Smad3 functions as a tumor suppressor and the expression of Smad3 is related to liver fibrosis and renal fibrosis, especially in a variety of kidney diseases, such as obstructive nephropathy, diabetic nephropathy, and hypertensive nephropathy.

Due to its unique features, Smad3-targeting PROTAC^® technology has recently attracted much attention. PROTAC^® is a bifunctional molecule that is designed to trigger Smad3 protein for degradation by hijacking the endogenous E3 ubiquitin ligase and the ubiquitin-proteasome system (UPS). The PROTAC^® development strategy not only provides a powerful tool for protein function studies in vivo but also a robust basis of using PROTAC^® for future clinical trials of cancer therapies.

Fig.1 Representative PROTAC^® of Smad3. (Sun, 2019)

Novel Ligand Design Services for Smad3-targeting PROTAC^®

Smad3 is an important signaling protein in renal fibrosis, the expression and function of Smad3 affect the signal transduction processes, including cell growth, proliferation, development, differentiation, and apoptosis. Generally, the strategy to construct a novel PROTAC^® small molecule is to degrade target proteins via ubiquitination. This may prevent kidney fibrosis by targeting ubiquitination, and the degradation of basic intracytoplasmic Smad3 is of great significance.

Based on different project requirements, there are multiple formats of ligands that we can develop through our PROTAC^® development platform for synthesizing and screening the most suitable ligands that bind to Smad3. We provide a list of services including but not limited to small molecule designed in silico docking screen, peptides and recombinant antibodies depending on phage display technology. Computer-aided drug design is often used to find a specific ligand targeting Smad3 and further verify and optimize screening results. The design of these ligands for the target protein with a recognition motif for E3 ligase and a linker is aimed to constitute novel functional PROTAC^® to prevent renal fibrosis by targeting Smad3 proteins.

Ligand Modification for Smad3-targeting PROTAC^®

From potency and safety consideration, it may require more effort to generate and identify a new suitable ligand; therefore, Creative Biolabs also provides modification and engineering of the existing ligands for Smad3. Thus, weak-affinity ligands or even those that bind to non-inhibitory sites on the protein target could be converted into potent PROTAC^® molecules with appropriate affinity. The generation of selective chemical compounds with potent effects provides valuable tools for biological target validation and with future potential for therapeutic application.

With years of experience, scientists at Creative Biolabs are pleased to offer the best ligand design service to develop a variety of PROTAC^®s against any target. If you are interested in learning more about our capacity for ligand design for Smad3-targeting PROTAC^®, please do not hesitate to contact us.

Reference

1. Sun, X.; et al. PROTAC^®s: great opportunities for academia and industry. Signal Transduction and Targeted Therapy. 2019, 4(1): 1-33.