Compared with traditional drugs, PROTAC molecules have many advantages. PROTAC molecule is covalently linked by the target protein ligand and E3 ubiquitin ligase ligand. After binding to the target protein, E3 ligase is recruited to form a stable ternary complex, which then undergoes proteasome-mediated degradation. In recent years, due to the popularity of PROTAC technology in the field of tumor drug development, researchers have developed a large number of small PROTAC molecules aimed at tumor targets. This paper mainly summarizes the latest progress of PROTAC technology in tumor-related target development and PROTAC molecular modification.
Tumorigenesis and tumor progression are attributed to the overexpression of proteins in a variety of signal pathways, including nuclear receptor proteins, kinase proteins, cell cycle regulatory factors, and other functional proteins. The development of PROTAC molecules that degrade these related proteins can inhibit the proliferation and migration of tumor cells and promote their senescence and apoptosis.
PROTAC Molecules Targeting Nuclear Receptors
AR protein is a key disease-related protein in metastatic castration-resistant prostate cancer (mCRPC). Previously, the treatment of mCRPC was usually achieved by small molecules, but the inhibitory effect of these small molecules decreased significantly with the amplification of AR gene and the emergence of drug-resistant mutations. PROTAC molecules based on target protein degradation can address these problems. At present, PROTAC molecules that inhibit AR 100 times higher than enzalutamide antagonists can effectively reduce AR regulation of gene expression. PROTAC molecules show a more prominent effect than inhibitors by down-regulating the level of AR protein through the degradation of AR, which provides an idea for developing mCRPC drugs.
PROTAC Molecules Targeting Epigenetic Proteins
Bromodomain and extraterminal domain (BET) protein family, as epigenetic regulatory factors related to tumors, play an important role in the occurrence and development of many kinds of tumors. Among them, BRD4 is an important transcriptional regulator that promotes the expression of c-MYC gene and causes tumor cell proliferation, differentiation, and metastasis. Inhibition of BRD4 can reduce proliferation and promote apoptosis of tumor cells, but the binding of inhibitors to target proteins is reversible, resulting in the unsatisfactory effects of BRD4 inhibitors.
The researchers linked BRD4 protein inhibitors to different E3 ligase ligands to obtain two kinds of PROTAC molecules. Compared with protein inhibitors, they more effectively reduce the level of BRD4 and downstream signal transduction, showing significant proliferation inhibition and apoptosis induction. Additionally, they significantly inhibit the development of acute lymphoblastic leukemia in animal experiments.
PROTAC Molecules Targeting Kinases
Protein kinases, a class of enzymes that catalyze protein phosphorylation, can transfer and covalently bind y-phosphate on adenosine triphosphate to serine, threonine, or tyrosine residual hydroxyl groups in specific protein molecules, thus changing the conformation and activity of substrate proteins and kinases. Protein kinase that involves in signal transduction and cell cycle regulation of tumor cells is an important regulatory factor of tumor cells.
PROTAC molecules have been well studied in regulating cyclin-dependent kinases for the treatment of prostate cancer, pancreatic cancer, acute myeloid leukemia, and other cancers, regulating a variety of leukemia caused by BCR-ABL fusion protein, and regulating the proliferation of tumor cells by Bruton tyrosine kinase. Compared with inhibitors, these PROTAC molecules for protein kinases show higher targeting, degrade one subtype without affecting the function of other related proteins, and greatly reduce their potential non-specific toxicity. For some mutants that are resistant to inhibitors, PROTAC molecules also present a good degradation effect, which solved the problem of drug-resistant mutation of proteins to some extent.
Targeting PROTAC Molecules of Other Proteins
The PROTAC molecule developed based on the human B-cell lymphoma xL protein (Bcl-xL) inhibitor makes use of the differential expression of E3 ligase in tumor cells and platelets to achieve tissue selectivity and boot tropism and reduce the platelet toxicity of Bcl-xL inhibitors. In addition, PROTAC molecules targeting PD-L1 can not only degrade PD-L1 to block its binding to PD-1, but also awaken the invasive ability of T cells, which can be used as a combination of cancer immunotherapy strategy.