A first-in-class experimental drug has shown strong preclinical activity against several aggressive blood cancers by exploiting a previously unrecognized relationship between two proteins that help malignant cells survive. The compound, GT19630, was designed to eliminate both MYC and GSPT1, two proteins that appear to reinforce one another in a molecular cycle. In laboratory and animal models of leukemia, lymphoma and multiple myeloma, disrupting this cycle reduced cancer-cell viability and produced substantial anti-tumor effects, including in models carrying TP53 mutations or resistance to standard therapies. The findings, led by researchers at The University of Texas MD Anderson Cancer Center, were published in Blood on August 17, 2026, under the title “Dual MYC and GSPT1 Protein Degrader for MYC-Driven Hematologic Malignancies.”
MYC has long been one of the most important and difficult targets in cancer biology. The protein acts as a transcriptional regulator, controlling networks of genes involved in cell growth, division, metabolism and protein production. Abnormally high MYC activity is estimated to contribute to approximately 70% of human cancers, allowing malignant cells to maintain the intense biosynthetic and metabolic demands of uncontrolled proliferation. Yet, despite decades of effort, conventional drugs have struggled to block MYC directly. The protein lacks a deep, easily accessible pocket where a traditional small-molecule inhibitor could bind, and its interactions with DNA and other regulatory proteins are complex and dynamic. As a result, MYC has frequently been described as “undruggable,” even though its central role in cancer has made it one of the field’s most sought-after therapeutic targets.
The new study identified a biological vulnerability that may make MYC indirectly accessible. Researchers found that MYC activates the gene encoding GSPT1, a protein involved in translation termination, the process by which ribosomes stop producing a protein after reaching a stop codon in messenger RNA. GSPT1, in turn, supports the production or maintenance of MYC protein in cancer cells. This reciprocal relationship creates what the investigators describe as a feedforward loop: MYC increases GSPT1, while GSPT1 helps sustain MYC. Such reinforcing circuits can make cancer cells unusually dependent on the continued presence of both proteins. Rather than attempting to inhibit MYC’s activity at a single molecular site, the researchers sought to collapse the system by removing the proteins themselves.
GT19630 belongs to a class of compounds known as targeted protein degraders. These drugs do not merely block a protein temporarily; they recruit the cell’s own protein-disposal machinery to mark a selected target for destruction. The tagged protein is recognized by the ubiquitin-proteasome system, a cellular recycling pathway that unfolds and breaks down unwanted or damaged proteins. According to the study, GT19630 binds to MYC and GSPT1 and promotes their degradation. The simultaneous loss of both proteins is important because targeting GSPT1 alone may not fully suppress MYC-driven biology. By interrupting the reinforcing cycle at two points, GT19630 caused a marked reduction in the levels of MYC and GSPT1, weakening the transcriptional and translational programs that support malignant growth.
The compound demonstrated activity across preclinical models representing multiple hematologic malignancies. Leukemia, lymphoma and multiple myeloma cells were highly sensitive to treatment, suggesting that the mechanism may apply broadly to cancers in which MYC activity is elevated. The effects were also observed in models containing alterations in TP53, a tumor-suppressor gene whose mutation is frequently associated with poor prognosis, resistance to treatment and disease relapse. TP53-mutated cancers often evade therapies that rely on intact cellular damage responses, making them particularly difficult to treat. The researchers’ results indicate that GT19630 may kill or suppress some of these cells through a mechanism that does not depend on restoring normal TP53 function.
One of the most notable findings involved acute myeloid leukemia, or AML, that had become resistant to venetoclax. Venetoclax targets the anti-apoptotic protein BCL-2 and has become an important component of treatment for several AML patients, but resistance can emerge as leukemic cells rewire their survival programs. In the resistant AML models examined in the study, MYC and GSPT1 levels were increased, suggesting that the feedforward loop may help sustain resistance. GT19630 reduced the abundance of both proteins and restored sensitivity to venetoclax in laboratory experiments. In one animal model, the combination produced a survival extension of more than 300% compared with the relevant control, a striking result for a preclinical study, although such findings cannot yet predict whether the same benefit will occur in patients.
The researchers also investigated leukemia stem-like cells, a population thought to survive initial treatment and contribute to relapse. These cells can retain self-renewal capacity and are often more resistant to conventional chemotherapy than the bulk of the leukemia. Analyses of individual cells showed that stem-like AML cells frequently contained higher MYC activity than normal blood-forming stem cells. Elevated MYC was also observed in stem cells from TP53-mutated AML. Because of this increased dependence, the malignant stem-like cells were more vulnerable to GT19630 in the study, while normal hematopoietic stem cells were less affected. The difference raises the possibility of a therapeutic window in which a degrader could preferentially damage leukemia cells while preserving a greater fraction of healthy bone-marrow function. However, the degree of selectivity and the potential for toxicity will need to be established through increasingly rigorous animal studies and, eventually, clinical trials.
The findings also illustrate a broader shift in drug development, from trying to inhibit every disease-driving protein with a conventional blocker to using the cell’s quality-control systems to remove proteins altogether. Protein degradation can overcome some limitations of traditional pharmacology, particularly when a target has a shallow binding surface or carries out its effects through multiple interactions. At the same time, degraders introduce their own challenges, including the need to achieve sufficient exposure in tumors, avoid unintended degradation of related proteins and manage effects in healthy tissues that depend on the same molecular pathways. GSPT1 participates in fundamental aspects of protein synthesis, and MYC regulates normal cell proliferation, so the safety profile of dual degradation will be a central question as development proceeds.
GT19630 has not yet been established as safe or effective in people, and the current evidence comes from preclinical cell and animal models. The next steps will include defining pharmacological properties, identifying dose limits, studying resistance mechanisms and determining whether MYC or GSPT1 activity can serve as a biomarker for patient selection. The investigators suggest that tumors with high MYC dependence may be especially responsive and that GT19630 could eventually be evaluated as a direct treatment for relapsed or resistant AML or in combination with venetoclax and other therapies. If future studies confirm the approach, dismantling the MYC–GSPT1 cycle could offer a new way to attack cancers that have resisted conventional treatment and provide a practical strategy for targeting a protein long regarded as beyond the reach of standard drugs.
Subject of Research: MYC- and GSPT1-targeted protein degradation in hematologic malignancies.
Article Title: Dual MYC and GSPT1 Protein Degrader for MYC-Driven Hematologic Malignancies
News Publication Date: August 21, 2026
Web References: https://www.mdanderson.org/ ; https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2025030170/570175/Dual-MYC-and-GSPT1-Protein-Degrader-for-MYC-Driven
References: Blood. DOI: 10.1182/blood.2025030170
Image Credits: The University of Texas MD Anderson Cancer Center
Keywords: MYC, GSPT1, GT19630, protein degrader, targeted protein degradation, leukemia, acute myeloid leukemia, lymphoma, multiple myeloma, TP53, venetoclax resistance, cancer research, hematologic malignancies, oncology, drug development
Tags: and multiple myelomaespecially those with TP53 mutations or therapy resistance.lymphomamaking it “undruggable.” This novel therapy leverages a different approach by degrading MYC and GSPT1 proteins simultaneouslyopening new avenues for treating resistant blood cancers such as leukemiatargetable binding pocket
