First-in-Class Drug Successfully Targets Undruggable MYC in Blood Cancers
Researchers at The University of Texas MD Anderson Cancer Center published a preclinical study in the journal Blood detailing a first-in-class experimental drug, GT19630, designed to target MYC, a protein long considered undruggable in hard-to-treat blood cancers. Led by Michael Andreeff, M.D., Ph.D., professor of Leukemia, and Yuki Nishida, M.D., Ph.D., assistant professor of Leukemia, the team discovered that GT19630 interrupts a feedforward loop between MYC and GSPT1. This mechanism successfully degrades both proteins, demonstrating strong anti-cancer activity across preclinical models of leukemia, lymphoma, and multiple myeloma, including treatment-resistant variants.
- The experimental protein degrader drug GT19630 successfully targets MYC, a master switch protein involved in approximately 70% of human cancers.
- Preclinical models showed that the therapy prolonged survival by more than 300% in certain acute myeloid leukemia models and restored sensitivity to venetoclax.
- The drug exploits a newly identified biological relationship between MYC and GSPT1, lowering levels of both proteins while sparing normal blood-forming stem cells.
Overcoming the Undruggable MYC Protein in Cancer Pathogenesis
For decades, the scientific community categorized the MYC protein as undruggable due to its central role in regulating genes that drive cell growth, division, and metabolic sustainability. According to findings published in Blood, researchers identified a previously unknown vulnerability involving the relationship between MYC and GSPT1. In this pathogenic cycle, MYC helps activate the GSPT1 gene, while GSPT1 assists cancer cells in producing more MYC proteins. GT19630 disrupts this feedforward loop by binding to both proteins and flagging MYC for disposal via the cell’s natural protein recycling system, while simultaneously degrading GSPT1.
Efficacy in Treatment-Resistant and TP53-Mutated Blood Cancers
Preclinical evaluations revealed high sensitivity to GT19630 across models of leukemia, lymphoma, and multiple myeloma. The drug maintained efficacy in cells carrying TP53 mutations, genetic alterations frequently associated with treatment resistance. Furthermore, the study addressed a critical barrier in acute myeloid leukemia (AML) therapy: resistance to venetoclax. Resistant AML cells exhibited elevated levels of MYC and GSPT1. Administration of GT19630 restored sensitivity to venetoclax and dramatically prolonged survival in preclinical models by over 300%.
Single-cell RNA analysis conducted during the study demonstrated that stem-like AML cells, which typically survive treatment and contribute to relapse, contain higher concentrations of MYC than normal blood-forming stem cells. This elevated dependence created a distinct therapeutic window where GT19630 selectively impacted treatment-resistant leukemia cells with minimal damage to healthy bone marrow.
Translational Promise and Future Clinical Pathways
The preclinical success of GT19630 establishes a scientific foundation for future clinical evaluations to determine safety and efficacy in human patients. Because cancers characterized by high MYC activity showed heightened vulnerability in the study, researchers suggest that future protocols may implement specific biomarkers to identify patient populations most likely to respond favorably. Additional research directions include evaluating GT19630 as a direct treatment for resistant or relapsed AML, or testing its efficacy in combination with other therapies.
*Disclaimer: The information provided in this article is for educational and scientific communication purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider regarding any medical condition, diagnosis, or treatment plan.*