G1-to-S phase transition protein 1 (GSPT1)

G1-to-S phase transition protein 1 (GSPT1), also known as eukaryotic release factor 3a (eRF3a), is a small GTPase and a critical component of the eukaryotic translation termination machinery [1, 2]. It works in complex with eRF1 to recognize stop codons and facilitate the release of nascent polypeptide chains from the ribosome [1, 3]. Beyond its role in translation, GSPT1 is essential for the transition of cells from the G1 to the S phase of the cell cycle and is involved in regulating apoptosis and the integrated stress response [1, 5]. In oncology, GSPT1 is frequently overexpressed and has been identified as a dependency in various malignancies, particularly acute myeloid leukemia (AML) and MYC-driven cancers such as small cell lung cancer [1, 11]. Because it lacks a traditional small-molecule binding pocket, GSPT1 was long considered "undruggable" until the advent of targeted protein degradation [2, 15]. Current therapeutic strategies utilize molecular glue degraders, such as CC-90009 and MRT-2359, which recruit GSPT1 to the cereblon (CRBN) E3 ubiquitin ligase complex, leading to its ubiquitination and subsequent proteasomal degradation [1, 7]. This degradation triggers catastrophic translation termination failure and apoptosis, offering a potent mechanism to combat aggressive, treatment-resistant tumors [11, 13].

Other names

eRF3aEukaryotic peptide chain release factor GTP-binding subunit ERF3AGST1Eukaryotic release factor 3aG1 to S phase transition 1

Molecular glue-mediated proteasomal degradation via CRL4-CRBN E3 ubiquitin ligase; activation of the integrated stress response; induction of TP53-independent apoptosis.