Discovery of new Lenalidomide derivatives as potent and selective GSPT1 degraders

Area of Science:

• Molecular Biology
• Oncology
• Drug Discovery

Background:

• G1 to S phase transition 1 (GSPT1) is essential for translation termination and functions as an oncogenic driver in various cancers.
• GSPT1 is a promising therapeutic target, but existing selective degraders have not yet received clinical approval.
• Developing novel, effective GSPT1 degraders is crucial for advancing cancer treatment strategies.

Purpose of the Study:

• To design and synthesize novel selective degraders targeting GSPT1.
• To evaluate the efficacy and mechanism of action of the lead compound, 9q.
• To assess the anti-cancer potential of compound 9q in relevant cancer cell lines.

Main Methods:

• Synthesis and screening of novel GSPT1 degraders.
• Determination of degradation efficiency (DC50) and selectivity using proteomic profiling.
• Investigation of the degradation pathway via the ubiquitin-proteasome system.
• Assessment of antiproliferative activity (IC50) and cell cycle effects (G0/G1 arrest, apoptosis).

Main Results:

• Compound 9q demonstrated potent GSPT1 degradation (DC50 = 35 nM) with good selectivity in U937 cells.
• Mechanism studies confirmed that 9q induces GSPT1 degradation through the ubiquitin-proteasome pathway.
• Compound 9q exhibited significant antiproliferative effects against U937, MOLT-4, and MV4-11 cancer cell lines (IC50 values in nanomolar range).
• 9q induced dose-dependent G0/G1 phase arrest and apoptosis in U937 cells.

Conclusions:

• Compound 9q is a highly effective and selective GSPT1 degrader.
• The ubiquitin-proteasome system mediates GSPT1 degradation induced by 9q.
• Compound 9q shows significant potential as an anti-cancer therapeutic agent by inhibiting proliferation and inducing cell death.