ADAM metallopeptidase domain 17 (ADAM17) is an enzyme that belongs to the ADAM protein family of metalloproteases. ADAM17 plays a prominent role in the Notch signaling pathway.

In this study, researchers demonstrated the discovery of ZLDI-8. ZLDI-8 is a novel inhibitor for Notch activating/cleaving enzyme ADAM-17. In particular, ZLDI-8 inhibits the cleavage of NOTCH protein. ZLDI-8 also decreases the expression of pro-survival and anti-apoptosis regulators, Survivin and cIAP1/2 (known as a cellular inhibitor of apoptosis 1/2), two downstream proteins in the Notch pathway. Moreover, ZLDI-8 inhibits the epithelial-mesenchymal transition (EMT) process of HCC cells.

Pre-treatment of ZLDI-8 enhances the susceptibility of hepatocellular carcinoma (HCC) cells to a small molecular kinase inhibitor Sorafenib, and chemotherapy agents Etoposide and Paclitaxel.

Furthermore, ZLDI-8 also enhances the effect of Sorafenib on inhibiting tumor growth in the nude HCC-bearing mice model. Especially, ZLDI-8 functions as sensitizer of Sorafenib in HCC treatment. ZLDI-8 enhances the antitumor effect of Sorafenib on in vivo metastasis of MHCC97-H and LM-3 cells.

ZLDI-8 (1 μM) significantly decreases the level of the Notch intracellular domain (NICD) and the accumulation of NICD in the nucleus. Treatment of ZLDI-8 significantly disrupted the activity of the Notch pathway in HCC cells and inhibited the epithelial-mesenchymal transition (EMT) process of HCC cells. ZLDI-8 also shows inhibitory activity against lymphoid-specific tyrosine phosphatase (Lyp, encoded by the PTPN22 gene) with a Ki of 26.22±4.77 μM. Protein tyrosine phosphatases (PTPs) play important roles in many human diseases, including inflammation, cancer, and metabolic and immunological disorders.

In summary, ZLDI-8 can be a promising therapeutic agent to enhance Sorafenib’s anti-tumor effect and to overcome the multi-drug resistance.

Zhang Y, et al. Novel ADAM-17 inhibitor ZLDI-8 enhances the in vitro and in vivo chemotherapeutic effects of Sorafenib on hepatocellular carcinoma cells. Cell Death Dis. 2018 Jul 3;9(7):743.