Undruggable to Degradable with AI

PROTAC is known as a new platform for disease treatment that has been difficult to reach with existing biopharmaceuticals. Deargen is accelerating the development of drugs through PROTAC by rapidly and precisely searching for small molecules that can bind to the target protein.

What is PROTAC (Proteolysis-targeting chimera)?

Proteolysis-targeting chimera (PROTAC) was introduced in 2001 by Kathleen Sakamoto, Craig Crews, and Ray Deshaies, based on ubiquitination to break down proteins in cells. It is the technology that ultimately induces the degradation of the target protein by artificially linking E3 ubiquitin ligase to a protein that the researcher targeted. 

Mechanisms of PROTAC

The core of PROTAC technology is to break down proteins through ubiquitination by E3 ubiquitin ligase. To achieve this, the following substances are needed: (a) a substance recruiting the E3 ubiquitin ligase, (b) a substance binding to the target of degradation protein, and (c) a substance connecting the two substances.

The advantage of PROTAC is that you can use a wide variety of partners, from small molecules to aptamers or even to the larger protein like antibodies bind to targets. So if a compound that can bind to an  Undruggable target is found, it can be easily applied. PROTAC technology can be applied even if drugs cannot enter the protein structure like the Tau tangle in Alzheimer’s and the c-Myc in cancer cells or there is no valid inhibitory binding position.

In addition, it has the advantages of overcoming existing drug resistance, sustained efficacy effect, and low dose use.

Status of PROTAC

Representative companies growing based on PROTAC technology are Arvinas, C4 Therapeutics, Nurix in the US and are mainly developing technology in collaboration with big pharmaceutical companies. For example, Arvinas is working with GSK, Genetech, Merck and Nurix with Celgene and C4 Therapeutics with Roche and Calico. Using this technology, Arvinas has a technology contract of about $ 745 million with Pfizer and about $ 587 million with Genetech, while C4 Therapeutics has a technology contract of about $ 676 million with Roche.

Arivinas is developing PROTAC-based therapies such as BET PROTAC, ARCC-44, and ARV-378, etc. that have the effects of treating cancers like hematological cancer, prostate cancer and breast cancer, etc. And technology is in the drug discovery and optimization process.

What We Do

Selecting of small molecules through PROTAC module 

The biggest bottleneck in PROTAC technology is to select substances that can bind to the protein for degradation. We are conducting research by screening targets skillfully and quickly with AI tools. We can also effectively design PROTAC few steps faster through selecting appropriate E3 ligases such as VHL, Cereblon, IAP, MDM2, etc. and effective binder ligands, screening small molecules for target degradation and even predicting additional effects and side effects as well as proteolysis by each factor with AI before PROTAC synthesis.

Collaboration with Uppthera Inc.

We has signed a technical agreement with Uppthera Inc. to apply and develop PROTAC to various diseases. 

Reference

[1] Paiva, S. L., & Crews, C. M. (2019). Targeted protein degradation: elements of PROTAC design. Current opinion in chemical biology, 50, 111-119.

[2] Smith, B. E., Wang, S. L., Jaime-Figueroa, S., Harbin, A., Wang, J., Hamman, B. D., & Crews, C. M. (2019). Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nature communications, 10(1), 131.

[3] Zou, Y., Ma, D., & Wang, Y. (2019). The PROTAC technology in drug development. Cell biochemistry and function, 37(1), 21-30.

[4] Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001). Protacs: chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. Proceedings of the National Academy of Sciences, 98(15), 8554-8559.