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Journal, PD(L)-1 Biomarker, IO biomarker: PRMT1 acts as a suppressor of MHC-I and anti-tumor immunity. (Pubmed Central) - Apr 1, 2024
Indeed, PRMT1 knockout or pharmacological targeting of type I PRMT with the clinical inhibitor GSK3368715 enhances Ifn?-induced MHC-I expression through elevated STAT1 expression and activation, while re-introduction of PRMT1 in PRMT1-deficient cells reverses this effect. Importantly, loss of PRMT1 enhances the efficacy of anti-PD-1 immunotherapy, and The Cancer Genome Atlas analysis reveals that PRMT1 expression in human melanoma is inversely correlated with expression of human leukocyte antigen molecules, infiltration of CD8+ T
- |||||||||| MS023 / University of Montreal, McGill University
Review, Journal: Targeting type I PRMTs as promising targets for the treatment of pulmonary disorders: Asthma, COPD, lung cancer, PF, and PH. (Pubmed Central) - Mar 12, 2024
Finally, we highlighted the physiological and pathological associations of type I PRMTs with asthma, COPD, lung cancer, PF, and PH. The developing of type I PRMTs modulators will be beneficial for the treatment of these diseases.
- |||||||||| MS023 / University of Montreal, McGill University
PRMT1 is a critical dependency in clear cell renal cell carcinoma with roles in post- transcriptional regulation and DNA damage response (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_5432;
Among the several promising targets identified, a particularly favorable inhibition profile was noted for MS023, an inhibitor of the type I protein arginine methyltransferase family (PRMT1/3/4/6 and 8)...This growth inhibition was corroborated using an additional type I PRMT compound, GSK3368715...Our data suggests that inhibition of PRMT1 inhibits processing of mRNA transcripts, compromises DDR mechanisms, leading to an accumulation of double stranded breaks, cytostasis and cell death. Thus PRMT1 represents a viable therapeutic target in ccRCC.
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Journal: PRMT1 inhibition promotes ferroptosis sensitivity via ACSL1 upregulation in acute myeloid leukemia. (Pubmed Central) - Jul 17, 2023
Additionally, the GSK3368715 treatment reduced the abundance of H4R3me2a, the main histone methylation modification mediated by PRMT1, in both genome-wide and ACSL1 promoter regions. Overall, our results demonstrated a previously unknown role of the PRMT1/ACSL1 axis in ferroptosis and suggested the potential value and applications of the combination of PRMT1 inhibitor and ferroptosis inducers in AML treatment.
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P1 data, Journal, Metastases: Phase 1 study of GSK3368715, a type I PRMT inhibitor, in patients with advanced solid tumors. (Pubmed Central) - Jul 14, 2023
P1
Overall, our results demonstrated a previously unknown role of the PRMT1/ACSL1 axis in ferroptosis and suggested the potential value and applications of the combination of PRMT1 inhibitor and ferroptosis inducers in AML treatment. Based on higher-than-expected incidence of TEEs, limited target engagement at lower doses, and lack of observed clinical efficacy, a risk/benefit analysis led to early study termination.
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Journal, PD(L)-1 Biomarker, IO biomarker: Inhibiting Type I arginine methyltransferase activity promotes the T cell mediated antitumor immune response. (Pubmed Central) - Apr 5, 2022
A type I PRMT inhibitor, GSK3368715, has been developed and has entered clinical trials for solid and hematologic malignancies...In immunocompetent mouse tumor models including a model of T cell exclusion, representing a common mechanism of PD1 resistance in humans, Type I PRMT inhibition increased T cell infiltration, produced durable responses dependent on CD8+ T cells and enhanced efficacy of anti-PD1 therapy. These data suggest Type I PRMT inhibition can potentiate an antitumor immunity in refractory settings.
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Biomarker, PK/PD data, Journal: Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues. (Pubmed Central) - May 11, 2021
Utilizing targeted mass spectrometry (MS), methods were developed to detect and quantitate changes in methylation of specific arginine residues on hnRNP-A1. This resulted in the development and validation of novel MS and immune assays useful for the assessment of GSK3368715 induced pharmacodynamic effects in blood and tumors that can be applied to GSK3368715 clinical trials.
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Trial completion, Enrollment change, Trial completion date, Trial primary completion date: First Time in Humans (FTIH) Study of GSK3368715 in Participants With Solid Tumors and Diffuse Large B-cell Lymphoma (DLBCL) (clinicaltrials.gov) - Mar 12, 2021
P1, N=31, Completed,
This resulted in the development and validation of novel MS and immune assays useful for the assessment of GSK3368715 induced pharmacodynamic effects in blood and tumors that can be applied to GSK3368715 clinical trials. Recruiting --> Completed | N=215 --> 31 | Trial completion date: Jul 2022 --> Mar 2021 | Trial primary completion date: Jul 2022 --> Mar 2021
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Journal: M-TAP Dance: Targeting PRMT1 and PRMT5 Family Members to Push Cancer Cells Over the Edge. (Pubmed Central) - Mar 22, 2020
In this issue of Cancer Cell, Fedoriw and colleagues characterize a potent reversible inhibitor of type I PRMTs, GSK3368715, with anti-proliferative effects on numerous cancer types. Using a combination of GSK3368715 with PRMT5 inhibitors, the authors show that a threshold of overall arginine methylation reduction needs to be achieved for synergistic anti-tumor activity.
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