FK506 binding proteins (FKBPs), also known as tacrolimus, are a family of immunophilins ubiquitously widely existing in eukaryotic organisms such as humans, plants, animals and yeast. As a cytosolic FKBP, FK506-binding protein 12 (FKBP12, or FKBP1A) is the smallest member and the most researched one among the identified mammalian FKBPs, which was named for its molecular weight of 12 kDa. Early in 1989, FKBP12 was characterized as the target or receptor of the immunosuppressive drug FK506 and Rapamycin, of which both molecules were noncovalently bound to FKBP12 to inhibit its PPIase activity.
Recently, FKBP12 has gained wide attention for its more than excellent immunosuppressive activity, but also participation in multiple biological processes, such as receptor signaling transduction, cellar activities, protein transportation, etc. It is all these critical functions that make FKBP12 a potential target for the treatment of diseases including cancers, neurodegenerative diseases, cardiac diseases, and other related diseases. Inhibition of FKBP12 activity by biochemical molecules, such as Rapamycin, specific antibodies, and novel proteolysis targeting chimera (PROTAC®), will be a valuable approach for disease therapy. As an expert in drug discovery, Creative Biolabs equips with professional scientists and advanced technology platforms to provide our valued clients comprehensive PROTAC® services.
Fig.1 Multiple functions of FKBP12. (Liu, 2013)
PROTAC® is a heterobifunctional molecule with the ability to induce protein degradation. Two ligands, one is for binding to the protein of interest (POI) and the other is an E3 ubiquitin ligase, connected by a linker to form a PROTAC® molecule. Unlike the usual enzyme/receptor inhibitors repressing or blocking the activity of target proteins, the PROTAC®s play an inhibitory role by directly degrading the target protein.
Fig.2 Mode of action of PROTAC®s. (Sun, 2019)
Accordingly, an FKBP12-targeting PROTAC® consists of a ligand specifically targeting FKBP12 protein and an E3 ubiquitin ligase. The FKBP12 protein would be ubiquitinated by E3 ubiquitin ligase once the POI ligand in PROTAC® recognized and bonded to FKBP12. Then, the ubiquitinated FKBP12 will be immediately recognized and degraded by the proteasome. In this way, the FKBP12-targeting PROTAC® exerts highly “inhibitory” effects on FKBP12 activity, which provides great potential for disease therapy at low doses.
As a senior biotech company in the field of drug discovery, Creative Biolabs is the first choice for your FKBP12-targeting PROTAC® design, characterization, and optimization.
FKBP12 has a relatively simple structure with only 108 amino acid peptides containing a minimal sequence for PPIase catalysis and drug binding. To date, several FKBP12-based PROTAC®s have been researched and developed. In terms of this potential therapeutic PROTAC®, in addition to the optimization and modification service of current FKBP12-related PROTAC®s, scientists at Creative Biolabs also provide solutions and services of novel FKBP12-targeting PROTAC® design.
Fig.3 FKBP12 is depicted as a cartoon with important residues shown as lines or with a Conolly surface. (Gerard, 2011)
For FKBP12-targeting PROTAC®s development, we can screen small chemical molecules as POI ligands based on the structural properties of the targets. Certainly, we also prefer to develop more potent and more specific POI ligands from antibody libraries, peptides, recombinant proteins, and other bioactive molecules. Our comprehensive one-stop PROTAC® services cover from initial design and production to later activity evaluation and verification.
Added by specially-constructed PROTAC® technical platform and experienced scientists, we are confident in providing high-quality PROTAC® services to global clients. Please directly contact us for more detailed information.
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