GSPT1 degraders are a novel class of therapeutic agents designed to combat various diseases, particularly cancer. These compounds eliminate disease-causing proteins rather than merely inhibiting their function. This approach offers a new pathway for treating conditions previously difficult to address.
Understanding GSPT1’s Role
GSPT1, or Guanine nucleotide triphosphate-binding protein 1, is a protein involved in fundamental cellular processes. It participates in mRNA translation termination, a step in protein synthesis that halts the creation of new proteins. GSPT1 also regulates the cell cycle, governing how cells grow and divide.
Dysregulation of GSPT1 function is linked to various diseases, including cancer. GSPT1 expression is elevated in certain cancer tissues and cell lines, such as liver and colon cancer. This overexpression can promote uncontrolled cell proliferation, migration, and invasion, making GSPT1 an attractive therapeutic target.
The Science of Targeted Protein Degradation
Targeted Protein Degradation (TPD) is a therapeutic strategy that aims to eliminate specific disease-causing proteins from cells. This differs from traditional drugs that often work by inhibiting a protein’s activity. TPD leverages the cell’s natural protein disposal system, known as the ubiquitin-proteasome system (UPS).
The UPS is responsible for tagging unwanted or damaged proteins with ubiquitin molecules, marking them for destruction by the proteasome, a cellular recycling machine. TPD agents, such as Proteolysis-Targeting Chimeras (PROTACs) or molecular glues, act as bridges. They bring the target protein into close proximity with an E3 ubiquitin ligase, an enzyme that adds ubiquitin tags. This induced proximity leads to the target protein’s ubiquitination and subsequent degradation by the proteasome.
How GSPT1 Degraders Work
GSPT1 degraders are bifunctional compounds with two distinct binding sites. One part binds to GSPT1, while the other recruits an E3 ubiquitin ligase, such as cereblon (CRBN).
When the degrader binds to both GSPT1 and the E3 ligase, it forms a “ternary complex,” bringing GSPT1 into direct contact with the degradation machinery. This proximity facilitates the transfer of ubiquitin tags onto GSPT1. Once tagged, GSPT1 is recognized by the proteasome, which then disassembles and recycles the protein. This catalytic process allows a single degrader molecule to destroy multiple GSPT1 proteins, leading to their elimination from the cell.
Therapeutic Applications
GSPT1 degraders hold promise for treating various diseases, particularly specific types of cancer. They are being explored for hematological malignancies, such as acute myeloid leukemia (AML) and multiple myeloma, where GSPT1 plays a role in disease progression. For example, in pediatric AML, GSPT1 degradation has shown effectiveness in subtypes driven by specific gene fusions, like RUNX1::RUNX1T1 and FUS::ERG, by reducing the levels of these leukemia-causing fusion proteins.
GSPT1 degraders offer advantages over traditional therapies. Their complete removal of target proteins can overcome drug resistance mechanisms developed by cancer cells against inhibitors. Additionally, GSPT1 degraders may allow for targeting proteins previously considered “undruggable” by conventional methods.
Current Development Landscape
GSPT1 degraders are currently in various stages of research and development. Many are undergoing preclinical studies, involving laboratory and animal testing to assess safety and effectiveness. Some have advanced to early-phase clinical trials, where they are tested in human volunteers.
For example, an orally active GSPT1 degrader, MRT-2359, is in a Phase 2 trial for MYC-driven tumors, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). GSPT1 degrader antibody conjugates, designed to deliver the degrader specifically to tumor cells, are also in clinical trials for breast cancer (ORM-5029) and AML (BMS-986497/ORM-6151). Ongoing research focuses on ensuring degrader specificity to minimize potential side effects and validate their safety and efficacy.