Targeting protein degradation based on PROTAC® is a very promising strategy for difficult-to-treat diseases. Thanks to our expertise in targeted protein degradation, Creative Biolabs offers excellent molecular discovery service for PROTAC® to eliminate pathological proteins. Our advanced PROTAC® platform enables robust discovery of therapeutic compounds with good biopharmaceutical properties that lead to effective protein degradation through proteasomes.
PROTAC® is an emerging strategy that has received widespread attention for therapeutic intervention. It is a heterobifunctional molecule that consists of a ligand for recruiting an E3 ligase, a linker, and a ligand that binds to the target protein for degradation. PROTAC® binds to both the target protein and E3 ligase simultaneously to induce the formation of a ternary complex. After recruiting E3 ubiquitin ligase, ubiquitin can be transferred from E2 to the target protein, resulting in ubiquitination and subsequent degradation of the target protein. PROTAC® has great potential to eliminate "undruggable" protein targets, including nuclear receptors, protein kinases, regulatory proteins, cellular metabolic enzymes, etc., which are not limited to physiological substrates of the ubiquitin-proteasome system. These findings indicate that PROTAC® has broad application prospects in the development of therapeutics.
Histone deacetylases (HDACs) are a class of proteases that remove acetyl groups on histone and non-histone proteins, and play a vital role in regulating gene expression and protein activity. HDAC6, belonging to the type II HDAC family, has unique structural and biological properties. HDAC6 has two functional deacetylation domains and one zinc finger motif, which is necessary for HDAC6 to exert its biological activity. In addition to deacetylation, HDAC6 is also involved in protein trafficking and degradation, cell shape and migration. The deregulation of HDAC6 is associated with a variety of diseases, such as cancers, neurodegenerative diseases, and autoimmune responses. Therefore, it is particularly important to directly control the level of HDAC6 protein in cells to achieve therapeutic purposes.
PROTAC® can achieve efficient degradation of interested proteins with excellent selectivity quickly and directly. To design novel HDAC6-targeting PROTAC®s, selective HDAC6 inhibitor Nexturastat A (Nex A) is used as the HDAC6 binder. According to the design principles of PROTAC®, Pomalidomide (Poma, a ligand for E3 ligase CRBN) is introduced into the end of the aliphatic chain of Nex A through different linkers. The designed PROTAC®s induce significant degradation of HDAC6 in a group of cell lines, showed excellent selectivity for other HDACs and therefore has effective cell proliferation inhibition.
Fig.1 The principle of PROTAC®. (An, 2019)
In order to develop ideal PROTAC® molecules with great potential to treat diseases, it is very important to design appropriate ligands for the effective degradation of disease-causing target proteins. Empowered by our experienced scientists and a proprietary target protein degradation platform, Creative Biolabs is committed to providing global pharmaceutical customers with comprehensive PROTAC® discovery services, from ligand design, optimization of the linker, to biological evaluation, to meet your drug discovery needs.
Our ligand design services for the target protein of interest can help scientists in their routine anti-tumor drug development and provide new drug identification and drug candidate evaluations to accelerate new drug development. If you want to know more, please feel free to contact us.
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