MKK3/MYC Protein-Protein Interaction Inhibitor Overcomes Resistant Non-Small Cell Lung Cancer

Application

A therapeutic use for SGI-1027 in the treatment of Osimertinib-resistant non-small cell lung cancer (NSCLC).

Key Benefits

• The MKK3/MYC protein-protein interaction inhibitor SGI-1027 effectively decreases MYC levels in Osimertinib-resistant NSCLC cell lines.
• The combination of SGI-1027 with Osimertinib offers synergistic benefits over either individual treatment.
• SGI-1027 combined with Osimertinib enhances apoptosis in resistant NSCLC cells.

Market Summary

Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases. Osimertinib is a third-generation EGFR tyrosine kinase inhibitor used for treating NSCLC with specific EGFR mutations. Resistance to Osimertinib inevitably develops in a significant proportion of patients (~30-40%), creating a need for alternative therapies or combination therapies.

Technical Summary

The MYC oncogene is a major regulator in cancer development and progression, making it a challenging target for drug development. Mitogen-activated protein kinase kinase 3 (MKK3) binds and activates MYC in various cell types. Dr. Ivanov has identified that SGI-1027 effectively decreases MYC levels and promotes MYC degradation in Osimertinib-resistant NSCLC by disrupting the MKK3/MYC protein-protein interaction. SGI1027 reduces c-Myc levels and, in combination with Osimertinib, decreases the survival of resistant NSCLC cell lines and NSCLC tumors in vivo. Developing novel therapeutic agents that target the MKK3/c-Myc interaction may have a high potential to improve the outcomes of MYC-driven cancers.

Publication Yang, X. et al. (2021). Bioorganic & Medicinal Chemistry, 45, 116324. https://doi.org/10.1016/j.bmc.2021.116324