A Novel ERK2 Degrader Z734 Induces Apoptosis of MCF-7 Cells via the HERC3/p53 Signaling Pathway.

Breast cancer is one of the leading causes of death worldwide, and synthetic chemicals targeting specific proteins or various molecular pathways for tumor suppression, such as ERK inhibitors and degraders, have been intensively investigated. The targets of ERK participate in the regulation of critical cellular mechanisms and underpin the progression of anticancer therapy. In this study, we identified a novel small molecule, which we named Z734, as a new mitogen-activated protein kinase 1 (ERK2) degrader and demonstrated that Z734 inhibits cell growth by inducing p53-mediated apoptotic pathways in human breast cancer cells. Treatment with Z734 resulted in the inhibition of cancer cell proliferation, colony formation and migration invasion, as well as cancer cell death via apoptosis. In addition, the Co-IP and GST pulldown assays indicated that the HECT and RLD domains containing E3 ubiquitin protein ligase 3 (HERC3) could directly interact with ERK2 through the HECT domain, promoting ERK2 ubiquitination. We also observed a strong link between HERC3 and p53 for the modulation of apoptosis. HERC3 can increase the protein and phosphorylation levels of p53, which further promotes apoptotic activity. In a xenograft mouse model, the effect was obtained in a treatment group that combined Z734 with lapatinib compared with that of the single-treatment groups. In summary, our results indicated that Z734 actively controls the development of breast cancer through apoptosis, and HERC3 may mediate ERK2 and p53 signaling, which offers new potential targets for clinical therapy.

A systematic review of the safety of tirzepatide-a new dual GLP1 and GIP agonist - is its safety profile acceptable?

Aims: Tirzepatide is a novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA). At present, there is no controversy over its effectiveness, but its safety. We conducted a systematic review to assess the safety of tirzepatide. Methods: We searched PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs) of tirzepatide from databases inception to August 28, 2022 and used the Cochrane Systematic Assessment Manual Risk of Bias Assessment Tool (version 5.1) and modified Jadad scale to assess risk of bias. The systematic review was conducted via Revman5.4. Results: Nine RCTs with a total of 9818 patients were included. The overall safety profile of tirzepatide is similar to GLP-1RAs, except for the hypoglycemia (tirzepatide 15mg, pooled RR=3.83, 95% CI [1.19- 12.30], P=0.02) and discontinuation (tirzepatide 10mg, pooled RR=1.75,95%CI[1.16-2.63], P=0.007 and 15mg, pooled RR=2.03, 95%CI [1.37-3.01], P=0.0004). It also showed that the dose escalation could not rise the occurrence rates of total, severe, gastrointestinal adverse events and hypoglycemia (P>0.05); Compared with 5mg, tirzepatide 10mg and 15mg were associated with more frequent nausea (P<0.001), discontinuation (P<0.05) and injection-site reaction (P<0.01); The rates of vomiting and diarrhea were dose-dependence at the range of 5-15mg. Conclusion: The safety profile of tirzepatide is generally acceptable, similar to GLP-1 RAs. It is necessary to pay attention to its specific adverse events (hypoglycemia and discontinuation) at high doses (10mg or higher). Nausea, vomiting, diarrhea, discontinuation and injection-site reaction were dose-dependence among specific dose ranges.As the heterogeneity in different studies by interventions, the results may be with biases and the further confirmation is needed. Meanwhile, more well-designed trials are needed to control the confounding factors and ensure adequate sample size.