Ligand for Target Protein

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PROTAC^® technology uses the ubiquitin-protease system to target and induce protein degradation in cells. Normally, ubiquitin-proteasome system functions to eliminate denatured, mutated or harmful proteins. Protacs’ highly efficient induction of target protein degradation has attracted the attention of many researchers from different fields, from oncology to neuroscience. Many studies have shown that degrading the oncoproteins is better than inhibiting their anticancer activity.

More than 30 proteins have been degraded using Protacs in different studies. Degradation of oncogenic proteins has become a feasible new strategy for treating cancer. Degradable target proteins include nuclear receptors (ER, AR, and RAR), protein kinases (Akt, BCR-Abl, c-Abl, BTK, ALK, CDK9, RIPK2, DAPK1, and PSD-95), protein transcription regulatory proteins ( BRD4, Sirt2, HDAC6, TRIM24, IKZH1/3, and Smad3), regulatory proteins (CRABP-I/II, TACC3, AHR, FKBP12, ERRα, and X-protein), neurodegeneration-related proteins (Tau, α- Synuclein and PSD-95), cell metabolic enzymes (MetAP-2 and DHODH), and fusion proteins (HaloTag).

Rapamycin has been shown to be a potent and specific ligand for FKBP12, which regulates mTOR signaling with high affinity (kd = 0.2nm). Therefore, we designed a PROTAC molecule that degrades FKBP12 by linking rapamycin (a FKBP12-specific ligand) and pomalidamine (a specific ligand that binds to CRBN-containing E3 protein ligase) via polyethylene glycol. This heterobifunctional molecule ubiquitinates FKBP12 via CR3B-containing E3 ligase, and degrades FKBP12 via the proteasome pathway. For target proteins that do not have a well-documented specific conjugate, developing PROTAC can be a challenge. However, since ligands only need to have a low affinity for the target protein to be sufficient for proteolysis using PROTAC, the Protacs strategy will provide more ways to achieve effective protein knockdown.

In the PROTAC drug development process, selective and effective protein of interest (POI) ligands are selected, combined with effective E3 ligand. Linker is optimized to maximize synergies, resulting in efficient and highly selective protein decomposers for optimal drug development opportunities. Currently, most of the reported Protacs are designed based on target protein binding ligands (usually inhibitors), because the crystal complex structure of the target protein and its binding ligand and the structure-activity relationship information of the ligand have been used to guide the design of PROTAC, such as determining the linker's connection position on the target protein binding ligand.

References:

1. Zorba A, et al.Delineating the role of cooperativity in the design of potent Protacs for BTK.Proc Natl Acad Sci U S A. 2018Jul 31;115(31):E7285-E7292.
2. Yutian, Zou, Danhui, Ma, Yinyin, & Wang. (2019). The Protac technology in drug development. Cell biochemistry and function.

* PROTAC^® is a registered trademark of Arvinas Operations, Inc., and is used under license.