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更新于：2026-07-18
GSK-3326595
更新于：2026-07-18
概要
基本信息
原研机构 |
非在研机构 |
最高研发阶段临床2期 |
首次获批日期- |
最高研发阶段(中国)临床前 |
特殊审评- |
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结构/序列
分子式C24H32N6O3 |
InChIKeyJLCCNYVTIWRPIZ-NRFANRHFSA-N |
CAS号1616392-22-3 |
关联
4
项与 GSK-3326595 相关的临床试验NCT04676516
A Phase II Randomized Window of Opportunity Trial Evaluating Clinical and Biological Effects of PRMT5 Inhibitor, GSK3326595, in Early Stage Breast Cancer
NCT03614728
A Phase I/II Study to Investigate the Safety and Clinical Activity of GSK3326595 and Other Agents in Participants With Myelodysplastic Syndrome and Acute Myeloid Leukaemia
NL-OMON53127
A phase I, open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK3326595 in subjects with solid tumors and non-Hodgkin*s lymphoma. - GSK3326595 (9018/0006)
100 项与 GSK-3326595 相关的临床结果
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100 项与 GSK-3326595 相关的转化医学
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100 项与 GSK-3326595 相关的专利（医药）
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43
项与 GSK-3326595 相关的文献（医药）2026-06-01Biomedical Journal
PRMT5-mediated methylation of LKB1 controls PD-L1 expression in NSCLC
Article
作者: Chen, Bo-Rong ; Tu, Chih-Yen ; Hsu, Jung-Mao ; Hu, Shu-Wei ; Chen, Po-Yu ; Wang, Bo-Wei ; Nguyen, Khuong T L ; Chen, Chia-Hung ; Wei, Ya-Ling ; Cheng, Fang-Ju ; Shen, Yi-Cheng ; Huang, Wei-Chien
BACKGROUND:
Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has significantly improved outcomes in non-small cell lung cancer (NSCLC), yet resistance remains a major clinical challenge. Protein arginine methyltransferase 5 (PRMT5) is an oncogenic regulator associated with poor prognosis, but its role in immune checkpoint modulation and underlying molecular mechanisms remain incompletely defined.
MATERIALS AND METHODS:
PRMT family expression and clinical correlations were analyzed using Oncomine, TCGA, and CPTAC databases. The effect of PRMT5 on PD-L1 was examined in LKB1-proficient and LKB1-deficient NSCLC cell lines using pharmacological inhibitors (GSK3326595, JNJ-64619178) and shRNA knockdown. Mechanistic analyses included co-immunoprecipitation (Co-IP), cycloheximide chase assays, and site-directed mutagenesis of LKB1 arginine residues. T-cell activation was evaluated using co-culture models.
RESULTS:
Elevated PRMT5 expression in NSCLC was associated with poor survival, reduced CD4+/CD8+ T-cell infiltration, and higher PD-L1 expression in clinical datasets. Functional analyses revealed context-dependent regulation of PD-L1 by PRMT5. PRMT5 inhibition reduced or failed to induce PD-L1 in LKB1-deficient cells but upregulated PD-L1 in LKB1-proficient cells. Mechanistically, PRMT5 interacted with LKB1 and promoted its degradation through symmetric arginine dimethylation at R409. Conversely, PRMT5 inhibition stabilized LKB1, activated AMPK signaling, and induced PD-L1 expression in LKB1-proficient cells. Combination treatment with a PRMT5 inhibitor and anti-PD-L1 antibody further enhanced T-cell activation in co-culture models.
CONCLUSION:
These findings identify a PRMT5-LKB1-AMPK regulatory axis controlling PD-L1 expression in a cell-context-dependent manner and suggest that LKB1 status may serve as a predictive biomarker for combining PRMT5 inhibitors with ICB in NSCLC. This strategy offers a potential therapeutic avenue to overcome immunotherapy resistance in LKB1-proficient NSCLC.
2026-06-01LEUKEMIA
PRMT5 inhibition sensitizes B-cell lymphoma cells to ferroptosis
Article
作者: Obernberger, Victoria A ; Tourdot, Taylor K ; Capitini, Christian M ; Rui, Lixin ; Wu, Sunny ; Petta, Sophie ; Ni, Qinyu ; Conyers, Madison J ; Zai, Zhuoyan ; Chen, Ruoyu ; Zhu, Fen ; Weerawardhene, Kavinu ; Liu, Yunxia ; Gao, Xiaoyue ; Bates, Paul D
Abstract:
Protein arginine methyltransferase 5 (PRMT5) is overexpressed in B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). While PRMT5 is known to regulate multiple oncogenic pathways, including PI3K-AKT signaling, its role in lipid metabolism and ferroptosis, a regulated, iron-dependent cell death driven by lipid peroxidation, remains poorly understood. Here, we identify a novel role for PRMT5 in suppressing ferroptosis in DLBCL and MCL cells through upregulation of SLC7A11, which imports cystine for glutathione (GSH) biosynthesis. This effect is mediated by the AKT-MYC-ATF5 signaling axis. ATF5, a MYC-regulated transcription factor overexpressed in these lymphomas, induces SLC7A11 expression. In addition, ATF5 promotes the expression of ATF4, another key regulator of the ferroptotic response, which forms heterodimers with ATF5 to further reinforce this regulatory network. PRMT5 inhibition sensitizes lymphoma cells to ferroptosis inducers such as dimethyl fumarate (DMF), an electrophile that irreversibly depletes GSH via succination. Notably, combined treatment with the PRMT5 inhibitor GSK3326595 and DMF synergistically enhances anti-tumor activity in a patient-derived xenograft (PDX) model. These findings reveal a previously unrecognized PRMT5-ATF5-SLC7A11 axis that drives ferroptosis resistance in B-cell lymphomas and provide a strong rationale for targeting PRMT5 to potentiate ferroptosis-based therapies in relapsed or refractory disease.
2026-03-02MOLECULAR PHARMACEUTICS
Preclinical Evaluation of
68
Ga-Labeled GSK3326595 for PRMT5 Expression with microPET-CT in Pan-Cancer
Article
作者: Li, Jindian ; Huang, Gang ; Liu, Xuwei ; Song, Shaoli ; Sun, Li ; Bai, Liyan
PRMT5, a member of the arginine methyltransferase family, is mainly distributed in the nucleus and cytoplasm and is closely involved in tumorigenesis, development, and metastasis. Based on GSK3326595, we first designed and synthesized a PRMT5-targeted precursor (DOTA-FZ-P5R). MOE simulation results indicated a strong binding affinity (KD ≈ 10-11) of DOTA-FZ-P5R toward PRMT5 (PDB: 4 × 61). The 68Ga-labeled tracer exhibited high RCP (>98%) and excellent stability. Western blot and cell uptake studies confirmed that PRMT5 was highly expressed in MDA-MB-231 and AsPC1 cells, while expression in A549 cells was comparatively low. Correspondingly, microPET-CT imaging demonstrated a significantly higher uptake of [68Ga]Ga-DOTA-FZ-P5R in MDA-MB-231 and AsPC1 tumor-bearing mice compared to A549. At 30 min postinjection, uptake values were 3.47 ± 1.53%ID/g for MDA-MB-231, 3.63 ± 0.81%ID/g for AsPC1, and 1.53 ± 0.25%ID/g for A549. These results were consistent with PRMT5 expression levels confirmed by IHC, further validating the tracer's specificity and potential for imaging PRMT5 expression in vivo. [68Ga]Ga-DOTA-FZ-P5R can dynamically visualize and quantify PRMT5 expression levels in real time across pan-cancer. This research demonstrates that [68Ga]Ga-DOTA-FZ-P5R enables rapid imaging of PRMT5-positive tumors. The probe has significant potential to enable individualized and precise diagnosis in patients with PRMT5-positive tumors, define an optimal treatment window, assess therapeutic efficacy, and serve as a predictive imaging modality for tumor resistance.
100 项与 GSK-3326595 相关的药物交易
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 早期乳腺癌 | 临床2期 | 加拿大 | 2021-06-08 | |
| 非霍奇金淋巴瘤 | 临床2期 | 美国 | - | 2021-04-12 |
| 急性髓性白血病 | 临床2期 | 美国 | 2018-10-16 | |
| 急性髓性白血病 | 临床2期 | 加拿大 | 2018-10-16 | |
| 骨髓增生异常综合征 | 临床2期 | 美国 | 2018-10-16 | |
| 骨髓增生异常综合征 | 临床2期 | 加拿大 | 2018-10-16 | |
| 星形细胞瘤 | 临床1期 | 美国 | 2016-08-30 | |
| 星形细胞瘤 | 临床1期 | 加拿大 | 2016-08-30 | |
| 星形细胞瘤 | 临床1期 | 法国 | 2016-08-30 | |
| 星形细胞瘤 | 临床1期 | 荷兰 | 2016-08-30 |
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临床结果
临床结果
适应症
分期
评价
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临床1期 | 288 | 鬱築窪願願襯衊廠醖網(鹽廠艱遞簾齋淵鑰積艱) = The most common adverse events at the RP2D included fatigue (57%), nausea (48%), and anemia (48%). 繭範蓋製鬱艱獵鏇壓觸 (壓鹽選蓋膚膚積範顧鏇 ) 更多 | 积极 | 2025-12-01 | |||
GSK3326595 monotherapy at RP2D (300mg or 400mg) | |||||||
临床1/2期 | 髓系肿瘤 U2AF1 | SRSF2 Mutation | 30 | GSK3326595 400 mg | 餘顧糧製網繭範選網餘(築範構廠鹽襯觸衊壓蓋) = 網觸鏇築簾繭鏇壓壓範 鏇艱築鏇窪繭齋艱壓淵 (網獵艱夢願範醖築膚繭 ) 达到 更多 | 不佳 | 2024-01-01 | |
临床1/2期 | 30 | (Part 1: GSK3326595 400 mg) | 範窪遞鏇餘憲醖鏇艱衊 = 壓窪窪獵鬱築簾範繭製 齋壓壓夢鑰糧獵簾鬱襯 (襯壓夢製顧窪艱繭夢廠, 艱鬱願網積糧構遞膚網 ~ 願鹽簾膚蓋淵鏇構蓋醖) 更多 | - | 2023-02-06 | ||
(Part 1: GSK3326595 300 mg) | 範窪遞鏇餘憲醖鏇艱衊 = 鹽積蓋蓋膚衊餘鏇願廠 齋壓壓夢鑰糧獵簾鬱襯 (襯壓夢製顧窪艱繭夢廠, 遞餘製繭窪繭選艱艱醖 ~ 膚獵範鹽廠廠夢壓鬱簾) 更多 | ||||||
临床1期 | 218 | (TNBC) | 鑰獵構網糧廠憲蓋鏇糧(淵蓋製構窪範獵廠築夢) = 製襯築顧蓋願糧鹽艱鹽 憲繭觸壓顧窪網繭繭築 (淵憲淵積獵鑰積醖網獵 ) | 积极 | 2022-09-12 | ||
(mTCC) | 鑰獵構網糧廠憲蓋鏇糧(淵蓋製構窪範獵廠築夢) = 鏇繭醖築淵艱夢鏇鏇齋 憲繭觸壓顧窪網繭繭築 (淵憲淵積獵鑰積醖網獵 ) | ||||||
临床1期 | 54 | 鬱鬱範蓋衊構獵鹽築構(鑰憲艱鹽壓鹽鹽憲範鬱) = anemia (n = 8 [15%]), thrombocytopenia, neutropenia, and fatigue (each n = 4 [7%]) 鏇蓋艱獵窪製觸鑰鏇醖 (窪積襯繭鬱鏇積鹹醖製 ) 更多 | 积极 | 2019-09-29 |
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