s727

Stattic (STAT3 Inhibitor V) is a STAT3 inhibitor (IC50=5.1 μM) that selectively inhibits STAT3 activation, dimerization, and nuclear translocation. Stattic has antitumor activity and induces apoptosis.

MK256 is a novel CDK8 inhibitor that demonstrates potent antitumor activity against AML by inhibiting the STAT pathway. It induces differentiation and maturation while inhibiting proliferation in AML cell lines. MK256 decreases the phosphorylation of STAT1(S727) and STAT5(S726) and reduces mRNA expression of MCL-1 and CCL2 in these cells. Its efficacy is validated in the MOLM-14 xenograft model, showing phosphorylation inhibition of STAT1(S727) and STAT5(S726) post-treatment. Pharmacokinetic studies in the MOLM-14 model reveal a dose-dependent inhibition of the STAT pathway. Both in vitro and in vivo studies confirm that MK256 effectively downregulates the STAT pathway.

SNX631 is a potent and highly selective CDK8/19 mediator kinase inhibitor with an IC₅₀ of 10.3 nM in NF-κB-dependent cellular assays. Its activity is 6–10 times higher than that of Senexin B in all assays except DiscoverX active site-dependent competitive binding experiments. SNX631 exerts synergistic effects with lapatinib and trastuzumab in multiple HER2-positive breast cancer cell lines, reversing and preventing resistance to HER2-targeted therapy. The combination of trastuzumab (a HER2 monoclonal antibody) and SNX631 inhibits the phosphorylation of STAT1 and STAT3 at the S727 site and upregulates the expression of the tumor suppressor BTG2 in HER2-positive breast cancer cells. SNX631 partially inhibits the growth of lapatinib-sensitive and -resistant HER2-positive breast cancer xenografts, and its antitumor effect is significantly enhanced when combined with lapatinib, effectively overcoming lapatinib resistance.

CDK8-IN-13 is a CDK8 inhibitor (IC50: 51.9 nM) with potent, selective and oral activity. CDK8-IN-13 induces apoptosis and reduces the expression of p-STAT1 S727 and p-STAT5 S726. CDK8-IN-13 exhibits anti-tumour activity.