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Dual MYC and GSPT1 Protein Degrader for MYC-Driven Hematologic Malignancies

Yuki Nishida1, Valeria Impedovo2, Edward Ayoub1

  • 1Section of Molecular Hematology and Therapy, Department of Leukemia, Houston, Texas, United States.

Blood
|August 17, 2026
PubMed

Insights

A new dual protein degrader, GT19630, effectively targets the MYC oncoprotein by degrading both MYC and GSPT1. This novel approach shows significant promise for treating MYC-driven hematologic malignancies, including resistant forms of leukemia and lymphoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Directly targeting the MYC oncoprotein has been a significant challenge in cancer therapy.
  • MYC plays a crucial role in various hematologic malignancies.
  • Understanding MYC regulatory pathways is key to developing effective treatments.

Purpose of the Study:

  • To introduce and characterize a novel dual protein degrader, GT19630, targeting MYC and GSPT1.
  • To investigate the mechanism of action of GT19630.
  • To evaluate the efficacy of GT19630 in preclinical models of hematologic malignancies.

Main Methods:

  • GT19630 was designed as a dual degrader for MYC and GSPT1.
  • The study analyzed the disruption of the MYC-GSPT1 feedforward loop.
  • In vitro and in vivo experiments were conducted using leukemia and lymphoma cell lines, primary samples, and animal models.

Main Results:

  • GT19630 disrupts a novel MYC-GSPT1 feedforward loop, inducing apoptosis via integrated stress response and TCA cycle inhibition.
  • The agent demonstrates superior activity over existing GSPT1 degraders, showing potent anti-proliferative effects and apoptosis at nanomolar concentrations.
  • GT19630 is highly active in vivo against therapy-resistant hematologic malignancies, including AML and multiple myeloma, and restores venetoclax sensitivity.

Conclusions:

  • GT19630 represents a promising therapeutic strategy for MYC-driven hematologic malignancies.
  • The dual targeting of MYC and GSPT1 offers a novel approach to overcome treatment resistance.
  • Further development of GT19630 is warranted for clinical application in patients with leukemia and lymphoma.

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