Last update 19 Sep 2024

GSPT2

Last update 19 Sep 2024

Basic Info

Synonyms

eRF3b, Eukaryotic peptide chain release factor GTP-binding subunit ERF3B, Eukaryotic peptide chain release factor subunit 3b

+ [4]

Introduction

GTPase component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons UAA, UAG and UGA (PubMed:15987998, PubMed:11524954, PubMed:17562865). GSPT2/ERF3B mediates ETF1/ERF1 delivery to stop codons: The eRF1-eRF3-GTP complex binds to a stop codon in the ribosomal A-site (PubMed:15987998). GTP hydrolysis by GSPT2/ERF3B induces a conformational change that leads to its dissociation, permitting ETF1/ERF1 to accommodate fully in the A-site (PubMed:15987998). Component of the transient SURF complex which recruits UPF1 to stalled ribosomes in the context of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons (PubMed:19417104).

Drugs associated with GSPT2

MDEG-541

Target

GSPT1 x GSPT2 x PLK1

Mechanism

GSPT1 modulators [+2]

Active Org.

Technische Universität München

Originator Org.

Technische Universität München

Active Indication

Gastrointestinal Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

FFT-135

Target

EF-1A x GSPT1 x GSPT2

Mechanism

EF-1A degraders [+2]

Active Org.

F5 Therapeutics, Inc.Startup

Originator Org.

F5 Therapeutics, Inc.Startup

Active Indication

Colorectal Cancer [+2]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SJ-6986

Target

CRBN x GSPT1 x GSPT2

Mechanism

CRBN modulators [+2]

Active Org.

St. Jude Children's Research Hospital, Inc.

Originator Org.

St. Jude Children's Research Hospital, Inc.

Active Indication

Acute Lymphoblastic Leukemia

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GSPT2

100 Translational Medicine associated with GSPT2

0 Patents (Medical) associated with GSPT2

Literatures (Medical) associated with GSPT2

15 Dec 2023·ACS Chemical Biology

Discovery of Molecular Glue Degraders via Isogenic Morphological Profiling

Article

Author: Ferrada, Evandro ; Superti-Furga, Giulio ; Koren, Anna ; Villanti, Ludovica ; Cisneros, Jose A ; Rukavina, Andrea ; Ng, Amanda ; Malik, Monika ; Winter, Georg E ; Hannich, J Thomas ; Offensperger, Fabian ; Kubicek, Stefan ; Scholes, Natalie S

Molecular glue degraders (MGDs) are small molecules that degrade proteins of interest via the ubiquitin-proteasome system. While MGDs were historically discovered serendipitously, approaches for MGD discovery now include cell-viability-based drug screens or data mining of public transcriptomics and drug response datasets. These approaches, however, have target spaces restricted to the essential proteins. Here we develop a high-throughput workflow for MGD discovery that also reaches the nonessential proteome. This workflow begins with the rapid synthesis of a compound library by sulfur(VI) fluoride exchange chemistry coupled to a morphological profiling assay in isogenic cell lines that vary in levels of the E3 ligase CRBN. By comparing the morphological changes induced by compound treatment across the isogenic cell lines, we were able to identify FL2-14 as a CRBN-dependent MGD targeting the nonessential protein GSPT2. We envision that this workflow would contribute to the discovery and characterization of MGDs that target a wider range of proteins.

17 Aug 2023·Blood

The orally bioavailable GSPT1/2 degrader SJ6986 exhibits in vivo efficacy in acute lymphoblastic leukemia.

Article

Author: Gao, Qingsong ; Ghate, Pankaj S ; Mishra, Ashutosh ; Goto, Hiroaki ; Chepyala, Divyabharathi ; High, Anthony A ; Akahane, Koshi ; Nishiguchi, Gisele ; Fischer, Marcus ; Yang, Lei ; Chang, Yunchao ; Peng, Junmin ; Iacobucci, Ilaria ; Yang, Jun J ; Keramatnia, Fatemeh ; Rankovic, Zoran ; Mullighan, Charles G

Advancing cure rates for high-risk acute lymphoblastic leukemia (ALL) has been limited by the lack of agents that effectively kill leukemic cells, sparing normal hematopoietic tissue. Molecular glues direct the ubiquitin ligase cellular machinery to target neosubstrates for protein degradation. We developed a novel cereblon modulator, SJ6986, that exhibits potent and selective degradation of GSPT1 and GSPT2 and cytotoxic activity against childhood cancer cell lines. Here, we report in vitro and in vivo testing of the activity of this agent in a panel of ALL cell lines and xenografts. SJ6986 exhibited similar cytotoxicity to the previously described GSPT1 degrader CC-90009 in a panel of leukemia cell lines in vitro, resulting in apoptosis and perturbation of cell cycle progression. SJ6986 was more effective than CC-90009 in suppressing leukemic cell growth in vivo, partly attributable to favorable pharmacokinetic properties, and did not significantly impair differentiation of human CD34+ cells ex vivo. Genome-wide CRISPR/Cas9 screening of ALL cell lines treated with SJ6986 confirmed that components of the CRL4CRBN complex, associated adaptors, regulators, and effectors were integral in mediating the action of SJ6986. SJ6986 is a potent, selective, orally bioavailable GSPT1/2 degrader that shows broad antileukemic activity and has potential for clinical development.

01 Feb 2022·Bioorganic Chemistry

A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer

Article

Author: Schneider, Carolin ; Kong, Bo ; Pongratz, Herwig ; Patricia Gloria Schäfer, Arlett ; Wirth, Matthias ; Heinzlmeir, Stephanie ; Öllinger, Rupert ; Krauß, Lukas ; Kuisl, Anna ; Lier, Svenja ; Engleitner, Thomas ; Saur, Dieter ; Schneeweis, Christian ; Kuster, Bernhard ; Bassermann, Florian ; Orben, Felix ; Hassan, Zonera ; Schlag, Christoph ; Reichert, Maximilian ; Dove, Stefan ; Sellmer, Andreas ; Schneider, Günter ; Mahboobi, Siavosh ; Rad, Roland

Targeted protein degradation offers new opportunities to inactivate cancer drivers and has successfully entered the clinic. Ways to induce selective protein degradation include proteolysis targeting chimera (PROTAC) technology and immunomodulatory (IMiDs) / next-generation Cereblon (CRBN) E3 ligase modulating drugs (CELMoDs). Here, we aimed to develop a MYC PROTAC based on the MYC-MAX dimerization inhibitor 10058-F4 derivative 28RH and Thalidomide, called MDEG-541. We show that a subgroup of gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.

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GSPT2

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