Dual MYC and GSPT1 Protein Degrader for MYC-Driven Hematologic Malignancies
Direct targeting of the oncoprotein MYC has not yet been successful. We here report a novel dual protein degrader, GT19630, which binds directly to MYC and G1 to S phase transition protein 1 (GSPT1). GT19630 disrupts a novel feedforward loop of MYC and GSPT1, where MYC promotes transcription of GSPT1, and GSPT1 senses the stop codon of MYC to properly terminate its translation. The agent induces integrated stress response and abrogates oxidative phosphorylation through inhibition of the TCA cycle, resulting in apoptosis. GT19630 has superior activity compared to GSPT1- targeting molecular glues. GT19630 induces profound anti-proliferative effects and apoptosis at low nanomolar concentrations in a multitude of leukemia and lymphoma cell lines and primary samples, including those with TP53 mutations. GT19630 is highly active in vivo in models of therapy-resistant hematologic malignancies, including Burkitt's lymphoma, acute myeloid leukemia (AML) and multiple myeloma. CD34+ AML blasts overexpress MYC protein compared to normal hematopoietic stem/progenitor cells (HSPCs) and GT19630 induces greater cytotoxicity in AML cells compared to normal HSPCs. Further, GT19630 restores sensitivity to venetoclax and profoundly prolongs survival in vivo in venetoclax-resistant AML. GT19630 was well tolerated in humanized Crbn mice. In conclusion, our data support the development of the MYC/GSPT1 degrader GT19630 as a therapeutic strategy of MYC-driven hematologic malignancies.
Authors
- Liang Tong (ORCID: https://orcid.org/0000-0002-0563-6468)
- Valeria Impedovo (ORCID: https://orcid.org/0000-0002-2166-4303)
- Ji Huang (ORCID: https://orcid.org/0000-0001-6547-9727)
- Stefano Tiziani (ORCID: https://orcid.org/0000-0002-7230-0307)
- Youzhi Tong
- Darah A Scruggs
- Sarita Namjoshi
- Koji Sasaki (ORCID: https://orcid.org/0000-0002-9140-0610)
- Sandeep Singh (ORCID: https://orcid.org/0000-0001-8780-5124)
- Eiji Sugihara (ORCID: https://orcid.org/0000-0002-3233-1045)
- Edward Ayoub (ORCID: https://orcid.org/0000-0003-1321-0114)
- Jo Ishizawa (ORCID: https://orcid.org/0000-0001-8566-7370)
- Hsu-Feng Chu (ORCID: https://orcid.org/0000-0001-6093-943X)
- Lauren B. Ostermann (ORCID: https://orcid.org/0000-0002-3330-2174)
- Natalia Baran (ORCID: https://orcid.org/0000-0003-0618-4798)
- John A. Tainer (ORCID: https://orcid.org/0000-0003-1659-2429)
- Mihai Gagea (ORCID: https://orcid.org/0000-0002-2399-1375)
- Steffen Boettcher (ORCID: https://orcid.org/0000-0001-9937-0957)
- Po Yee Mak
- Hideaki Mizuno (ORCID: https://orcid.org/0000-0002-6983-5255)
- Abhishek Maiti (ORCID: https://orcid.org/0000-0001-9043-538X)
- Thomas Van Huynh
- Kazuharu Kamachi (ORCID: https://orcid.org/0000-0002-7346-4864)
- Michael Andreeff (ORCID: https://orcid.org/0000-0002-1144-1958)
- Zamal Ahmed (ORCID: https://orcid.org/0000-0003-3400-6577)
- Andrea Bedoy (ORCID: https://orcid.org/0009-0001-4937-4527)
- Shayaun Khazaei (ORCID: https://orcid.org/0009-0004-2677-8176)
- Dong Chen (ORCID: https://orcid.org/0000-0001-7627-9560)
- Honghua Yan
- Liandong Ma
- Tetsuya Takimoto (ORCID: https://orcid.org/0009-0009-3008-8078)
- Liang Zhang
- Yuki Nishida
- Branko Cuglievan
- Bing Z Carter
- Torsten Haferlach
Institutions
- Texas Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Fujita Health University (JP)
- Saga University (JP)
- University of Zurich (CH)
- Alabama College of Osteopathic Medicine (US)
- University Hospital of Bern (CH)
- Munich Leukemia Laboratory (Germany) (DE)
- University Hospital of Zurich (CH)
- Luye Pharma (China) (CN)
- Cellular Research (United States) (US)
- Io Therapeutics (United States) (US)
- Institute of Science Tokyo (JP)
- Columbia University (US)
- The University of Texas at Austin (US)
Publication Details
- Journal
- Blood
- Published
- 2026-08-17
- DOI
- https://doi.org/10.1182/blood.2025030170
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00