Ligand Design for CDK9-targeting PROTAC^®

Creative Biolabs, the pioneer of targeted protein degradation technology, has turned targeted protein degradation into one of the most promising areas of drug discovery for various diseases. Empowered by our experienced team and advanced drug discovery platform, Creative Biolabs is engineering an expansive pipeline of proteolysis targeting chimeras (PROTAC^®) protein degraders to harness the natural ubiquitin-proteasome system. We provide CDK9 ligand development and identification services for global clients.

Introduction of CDK9

The CDKs are a family of more than 13 serine-threonine kinases. CDK9 is a serine/threonine kinase that forms a subunit of the positive transcription elongation factor b (P-TEFb) complex with cyclin T. CDK9 could interact with many transcription factors (TFs) and regulate the expression of anti-apoptotic proteins for the survival of cancer cells. There are two isoforms of CDK9, a 42 KDa and a 55 kDa protein. CDK9 is ubiquitously expressed and has been shown to play an important role in the pathogenesis of various malignancies, such as acute myeloid leukemia (AML), osteosarcoma, prostate, pancreatic, and breast cancers. Due to its ability to regulate the transcription of anti-apoptotic short-lived proteins, CDK9 is suggested as a promising therapeutic target in oncology. Knockdown or degradation of CDK9 presents a promising strategy to potently and selectively ablate the kinase activity. Selective targeting CDK9 by designing PROTAC^® would be a promising new approach in cancer therapy.

Fig.1 Regulation of transcription by CDK9. (Rahaman, 2016)

At present, the most prominent method of blocking the P-TEFb function is to directly inhibit the ATP-binding site of CDK9. However, the ATP binding pocket is conserved in the whole CDK family, this strategy is not the most specific for drug discovery. Thus, other approaches have been designed in order to increase the selectivity of CDK9 inhibitors. One example is done by 5,6-dichlorobenzimidazone-1-β-D-ribofuranoside (DRB). DRB blocks the ATP binding site of CDK9 by halogen bond formation, inducing conformational changes in the glycine-rich loop of CDK9. Besides, two peptide sequences were identified as potential inhibitors by directly interfering with the CDK9/Cyclin T1 complex formation.

Small Molecule-based CDK9-targeting PROTAC^®

It is known that the PROTAC^® strategy requires an appropriately placed surface-exposed lysine residue for ubiquitination and proteasome degradation. The shape of the surface and the distribution of lysine residues on the surface among the CDK family members are different, providing a unique opportunity to develop a selective CDK9 degrader. A small-molecule ligand-based PROTAC^® has more potential of being developed into a drug because a small molecule is easier for the human body to absorb than the peptide or antibody.

Fig.2 A schematic diagram of the small molecule-based PROTAC^®s. (Zou, 2019)

CDK9 Ligand Development Services

Many attempts have been made by Creative Biolabs to design different types of ligand for CDK9-targeting PROTAC^® development. To date, a series of ligands against CDK9 has been designed by using our featured aminopyrazole and aminothiazole scaffold. For example, wogonin is a natural product that has been proved to be a potent and selective inhibitor of CDK9. By using the wogonin scaffold as the ligand, Creative Biolabs has produced the CDK9 degrader by conjugation of the wogoni scaffold to the thalidomide derivative and pomalidomide.

What Can We Do for You?

• Providing various aminopyrazole, aminothiazole and wogonin scaffold-based ligands targeting CDK9.
• Enable to develop multiple ligand types, including small molecules, peptides, proteins, as well as antibodies.
• To improve efficacy and reduce toxicity, Creative Biolabs designs and further optimizes small molecule ligands not only targeting CDK9 but also other CDKs.
• Creative Biolabs is capable of developing the dual-degrader which inhibits cell proliferation.
• Rapid affinity identification of ligand candidates for CDK9.
• Structural modification to optimize the CDK9 ligand to improve the stability, biodistribution, and penetrability in vivo.

CDK9 has emerged as a druggable target for the development of cancer therapeutics. Creative Biolabs offers custom services for the design and synthesis of ligands for your CDK9 degradation research. If you are interested in our ligand design services, please feel free to contact us for more detail.

References

1. Rahaman, M. H.; et al. Targeting CDK9: a promising therapeutic opportunity in prostate cancer. Endocrine-related cancer. 2016, 23(12): T211-T226.
2. Zou, Y.; et al. The PROTAC^® technology in drug development. Cell biochemistry and function. 2019, 37(1): 21-30.