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| Targets |
GSPT1 (IC50 = 30~300 nM)
GSPT1 (G1 to S phase transition 1), also known as eRF3a, is a eukaryotic translation termination factor. MRT-2359 induces the degradation of GSPT1 by acting as a molecular glue that promotes the interaction between GSPT1 and the E3 ubiquitin ligase substrate receptor, leading to its ubiquitination and subsequent proteasomal degradation. This targeted protein degradation mechanism results in the inhibition of protein synthesis. GSPT1 is a synthetic lethal target in MYC-driven cancers, making MRT-2359 a promising therapeutic strategy for these malignancies. |
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| ln Vitro |
MRT-2359 was rationally designed using the QuEENTM discovery engine and optimized to achieve a profound and preferential antiproliferative activity in MYC-driven cell lines, such as high N- and L-MYC mRNA expressing non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) lines. In line with expectations, MRT-2359 activity is dependent on both CRBN and the GSPT1 G-loop degron. We further demonstrate using an inducible system that the sole expression of either N- or L-MYC is sufficient to sensitize initially resistant NSCLC cells to MRT-235. Mechanistically, RiboSeq and polysome profiling revealed that treatment with MRT-2359 in the N- or L-MYC high cell lines induces ribosome stalling at the stop codon, increased monosomes and decreased polysomes. These changes are indicative of translational repression and were confirmed using puromycilation assays. Proteomics and RNAseq studies finally demonstrated a significant reduction in the total levels of N- or L-MYC leading in turn to the downmodulation of MYC target genes. Despite robust degradation of GSPT1, no marked effect was observed in these assays in low N- or L-MYC lines, confirming the selective activity of MRT-2359 in MYC-driven lung cancers. [1].
MRT-2359 exhibits potent anti-proliferative activity in vitro against a range of cancer cell lines. It has an IC50 of >30 nM and <300 nM in inducing GSPT1 degradation. In the CAL51 cell line, it achieves a DC50 (concentration for 50% degradation) of 5 nM with a Dmax (maximum degradation) of 100%. It preferentially targets MYC-driven cell lines, including drug-resistant NSCLC and SCLC cells. It induces apoptosis dependent on protein translation inhibition. |
| ln Vivo |
the anti-tumor activity of MRT-2359 was assessed in >80 lung patient-derived xenografts (PDXs). MRT-2359 demonstrated preferential activity in N- and L-MYC high NSCLC and SCLC PDXs, including numerous instances of tumor regressions, when dosed orally daily or intermittently. Similar levels of anti-tumor activity were also observed in neuroendocrine lung cancer and lymphoma PDXs [1].
In vivo, MRT-2359 has demonstrated antitumor activity in preclinical models. It is orally active and has shown efficacy in inhibiting the growth of tumors, including those that are resistant to standard therapies. Its activity is particularly pronounced in MYC-driven models, where it suppresses tumor progression through GSPT1 degradation and subsequent inhibition of protein synthesis. |
| Enzyme Assay |
The in vitro activity of MRT-2359 is typically assessed using cell viability and proliferation assays. Cancer cell lines are treated with varying concentrations of MRT-2359 for 72-120 hours. Cell viability is measured using ATP-based luminescent assays (e.g., CellTiter-Glo) to determine the half-maximal inhibitory concentration (IC50). Target engagement is confirmed by measuring GSPT1 protein levels via Western blot to determine the DC50 (concentration for 50% degradation).
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| Cell Assay |
MRT-2359, which has been rationally designed and optimized to selectively induce apoptosis in translationally addicted cells. MRT-2359 promotes complex formation between CRBN and GSPT1 and potently induces GSPT1 degradation in a CRBN- and degron-dependent manner. The high selectivity of MRT-2359 was subsequently demonstrated by the lack of activity in cells expressing a non-degradable GSPT1 mutant. Although MRT-2359 degrades GSPT1 in all the cell lines tested, profiling in a large panel of cancer lines revealed profound and preferential antiproliferative activity in Myc-driven cell lines, such as high N-Myc expressing non-small cell lung cancer (NSCLC) lines and high L-Myc expressing small cell lung cancer (SCLC) lines. In the Myc-driven cells, degradation of GSPT1 led to translational repression as manifested by a global shift from polysomes to monosomes resulting in the reduction of a subset of proteins as assessed by quantitative proteomics. In particular, N- or L-Myc protein levels decreased and as a consequence the known Myc target genes were downregulated at the mRNA level. Despite the robust degradation of GSPT1, no marked effect was observed in low N-Myc lines, confirming the selective activity of our GSPT1 degrader in Myc-driven lung cancers [2].
To study its cellular effects, cancer cell lines are treated with MRT-2359, and protein synthesis is measured using techniques like puromycin incorporation or O-propargyl-puromycin (OPP) labeling. Apoptosis is assessed by measuring caspase-3/7 activity or by Annexin V staining. The expression of GSPT1 and downstream markers of protein translation inhibition, such as ATF4, is analyzed by Western blot. |
| Animal Protocol |
Oral administration of MRT-2359 in high N-Myc NSCLC xenografts and PDXs led to complete intratumoral GSPT1 degradation and concomitant decrease in N-Myc protein levels, resulting in tumor regression. In contrast, MRT-2359 had limited or no activity in low N-Myc NSCLC models, further corroborating the selective vulnerability of Myc-driven tumors to GSPT1 degradation [2].
In immunocompromised mice, xenografts of the AR-V7-positive cell line 22RV1 and the neuroendocrine prostate cell line NCI-H660, both of which are sensitive to MRT-2359 in vitro, were treated with several MRT-2359 dose regimens including continuous as well as intermittent (5 days on/9 days off) dosing. Most regimens led to marked tumor regression. Tumors of both models fully regressed after a 4-week course of 10 mg/kg MRT-2359 once daily, and no tumor regrowth could be detected after cessation of treatment. No significant in vivo response was observed for xenografts of the insensitive cell line PC-3 [3]. The in vivo efficacy of MRT-2359 is evaluated in mouse xenograft models of NSCLC and SCLC. Tumor-bearing mice are treated orally with MRT-2359 at various doses and schedules. Tumor volume is measured, and at the endpoint, tumors are harvested for analysis of GSPT1 degradation, protein synthesis inhibition, and apoptosis. |
| ADME/Pharmacokinetics |
MRT-2359 has a molecular weight of 495.38 g/mol and a molecular formula of C22H17F4N3O6. It is an orally bioavailable small molecule. Specific pharmacokinetic parameters, such as half-life and bioavailability, are proprietary but are typical of orally administered small-molecule drugs. It is formulated for oral administration in preclinical studies.
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| Toxicity/Toxicokinetics |
Toxicological data for MRT-2359 are primarily from preclinical studies. As with all targeted protein degraders, its safety profile is a key consideration in its development. The most common adverse effects are expected to be related to its mechanism of action, including gastrointestinal and hematological toxicities due to the inhibition of protein synthesis. Comprehensive safety data are being generated in ongoing clinical trials.
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| References |
[1]. Development of MRT-2359, an orally bioavailable GSPT1 molecular glue degrader, for the treatment of lung cancers with MYC-induced translational addiction[J]. Cancer Research, 2023, 83(7_Supplement): 3449-3449.
[2]. Abstract 3929: Identification of MRT-2359 a potent, selective and orally bioavailable GSPT1-directed molecular glue degrader (MGD) for the treatment of cancers with Myc-induced translational addiction. Cancer Res 15 June 2022; 82 (12_Supplement): 3929. [3]. Abstract 3294: The GSPT1 molecular glue degrader MRT-2359 is active against prostate cancer. Cancer Res 15 March 2024; 84 (6_Supplement): 3294. |
| Additional Infomation |
As an orally bioavailable selective molecular glue degrader (MGD), MRT-2359 targets the translational termination factor GSPT1 and holds potential antineoplastic activity. Upon oral administration, MRT-2359 binds to GSPT1, promoting its association with cereblon (CRBN), a component of the E3 ubiquitin ligase complex, and inducing CRBN‑ and degron‑mediated degradation of GSPT1. This degradation suppresses L‑MYC and N‑MYC levels, disrupting MYC‑driven protein translation and attenuating MYC oncogenic signaling, thereby inhibiting proliferation in MYC‑driven tumors. GSPT1, a G‑loop degron‑containing protein, is essential for protein translation in MYC‑expressing cancers.
MRT-2359 is an investigational drug currently under clinical development for the treatment of advanced solid tumors, including MYC-driven NSCLC and SCLC. Its unique mechanism of action as a GSPT1 molecular glue degrader represents a novel approach to targeting protein synthesis in cancer. Preclinical studies have shown that it is effective in both treatment-naïve and drug-resistant models, highlighting its potential to overcome therapeutic resistance. It is not yet approved for clinical use. |
| Molecular Formula |
C22H17F4N3O6
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| Molecular Weight |
495.380499601364
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| Exact Mass |
495.11
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| Elemental Analysis |
C, 53.34; H, 3.46; F, 15.34; N, 8.48; O, 19.38
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| CAS # |
2803881-11-8
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| PubChem CID |
164584214
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| Appearance |
White to off-white solid
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| LogP |
2.5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
35
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| Complexity |
856
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(OCC1C=CC2=C(C=1)C(=O)N(C1CCC(=O)NC1=O)C2)(=O)NC1=CC(OC(F)(F)F)=CC=C1F
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| InChi Key |
HNTGMIGBGVFOBT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H17F4N3O6/c23-15-4-3-13(35-22(24,25)26)8-16(15)27-21(33)34-10-11-1-2-12-9-29(20(32)14(12)7-11)17-5-6-18(30)28-19(17)31/h1-4,7-8,17H,5-6,9-10H2,(H,27,33)(H,28,30,31)
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| Chemical Name |
(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl (2-fluoro-5-(trifluoromethoxy)phenyl)carbamate
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| Synonyms |
MRT-2359; GTPL12629; MRT 2359;
MRT-2,359; 2803881-11-8; MRT2,359; [2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]methyl N-[2-fluoro-5-(trifluoromethoxy)phenyl]carbamate; M2R4A9NKZ8; MRT2359
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 100 mg/mL (201.87 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.05 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0187 mL | 10.0933 mL | 20.1865 mL | |
| 5 mM | 0.4037 mL | 2.0187 mL | 4.0373 mL | |
| 10 mM | 0.2019 mL | 1.0093 mL | 2.0187 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Link: https://clinicaltrials.gov/ct2/show/NCT05546268
Conditions:NSCLC|SCLC|High Grade Neuroendocrine Cancer|DLBCL|L-MYC and N-MYC Amplified Solid Tumors|NSCLC With High or Low L-MYC or N-MYC Expression|HR-positive, HER2-negative Breast Cancer|Prostate CancerProducts are for research use only; We do not sell to patients
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