The occurrence and development of cancer is a complex process, which is characterized by continuous proliferation signals, avoidance of growth inhibitors, resistance to cell death, induction of angiogenesis, activation of invasion and metastasis. Studies have shown that some overexpressed and/or overactivated proteins play a key role in tumorigenesis and are potential targets for cancer therapy. Therefore, proteolysis-targeting chimera (PROTAC) is widely used in targeted cancer therapy.
Targeting Tumor Cell Proliferation
Growth-promoting signals, including RAS-RAF-MEK-ERK pathway, are often overactivated in tumors, promoting cell cycle progression to induce uncontrolled cell proliferation. PROTAC technology has been used to target overexpressed, overactivated, or mutated proteins involved in cell cycle regulation.
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BRD4
BRD4, a member of the bromine domain and hyperterminal domain (BET) family proteins, is an epigenetic reader of histone acetylation and can induce the transcription of proliferation-promoting genes (such as c-Myc). Small molecular inhibitors of BRD4, including JQ1 and BETi-211, can down-regulate the level of c-Myc and induce effective anti-proliferation response. However, high doses of BRD4 inhibitors are required to ensure BRD4 inhibition, and the anti-tumor effect is not satisfactory only by blocking the bromine domain of BRD4.
In the study targeting BRD4, the researchers found that the appropriate length of PROTAC junction fragments can enhance the synergism between BRD4 and VHL, and then give PROTAC the selectivity to BRD4. The favorable BRD4-CRBN binding conformation can be produced by adjusting the length of the connecting fragment and the modification site.
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CDK4/CDK6
Cyclin-dependent kinase (CDK) controls cell cycle progression in response to extracellular proliferation signals. Among them, CDK4/6 phosphorylates retinoblastoma protein (Rb) and activates E2F transcription factors to promote gene transcription and mediates the transition from G1 to S phase of cell cycle. In cancer cells, CDK4/6 is usually overactivated by its upstream oncogenes, such as c-Myc, and is used as a potential target for cancer therapy.
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AURKA
Aurora kinase A (AURKA) can drive centrosome separation to induce cell cycle from G2 phase to M phase. In the mouse model, overexpressed AURORA-A can transform normal epithelial cells into cancer cells, highlighting AURORA-A as a potential cancer target. Alisertib, a potent AURORA-A inhibitor, is being studied in a number of clinical trials. In addition to the catalytic activity, AURORA-A also has an additional non-catalytic function that conventional small molecules are difficult to target, which explains why the therapeutic effect is poor in some trials.
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EGFR
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK), which can activate a variety of carcinogenic signals and promote cell proliferation and differentiation. EGFR overactivation or acquired functional mutations are common in breast cancer, lung cancer, and other epithelial cancers. A variety of EGFR inhibitors, such as gefitinib, rapatinib, and afatinib, have been approved for cancer treatment, but the severe resistance of EGFR inhibitors leads to low clinical response, which may be caused by drug-induced EGFR mutations.
In general, the selectivity of PROTAC based on EGFR inhibitors is consistent with that of its parent inhibitors, so it is necessary to classify EGFR before PROTAC treatment.
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BRAF
RAF family kinase is a key regulator of RAS-RAFMEK-ERK pathway, which transmits cancer signals to promote cell proliferation. Acquired functional mutations of RAF, such as BRAFV600E, are powerful drivers of human cancer. BRAFV600E inhibitors show good efficacy in cancer treatment, but the long-term effectiveness is limited by RTK and/or RAS activation or BRAF secondary mutation. PROTAC provides an alternative strategy for limiting oncogenic BRAF therapy.
In addition to the above-mentioned targets, PROATC can also target the following proteins related to cancer cell proliferation: AR, ALK, BLK, BRD7/9, CDK2/5, CDK8, CDK9, Cdc20, c-Met, CREPT, CYP1B1, DHODH, ER, ERK1/2, FLT-3, HER2, MEK1/2, KRASG12C, GSPT1, PLK1, SLC9A1, TACC3, TRIM24, TRKA/C, Wee1, α 1A-AR.