期刊
ONCOTARGET
卷 8, 期 25, 页码 39963-39977出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.18102
关键词
AlphaLISA; colorectal cancer; pancreatic ductal adenocarcinoma; PRMT5; small-molecule inhibitor
资金
- Indiana Center for Technology and Science Innovation (CTSI)
- Indiana Drug Discovery Alliance (IDDA) [2286230, 2286233]
- Indiana University Pancreatic Cancer Signature Center [4189911 MUR1]
- V foundation Kay Yow Cancer Fund [4486242]
- National Cancer Institute [CA-075059]
Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are notoriously challenging for treatment. Hyperactive nuclear factor.B (NF-kappa B) is a common culprit in both cancers. Previously, we discovered that protein arginine methyltransferase 5 (PRMT5) methylated and activated NF-kappa B. Here, we show that PRMT5 is highly expressed in PDAC and CRC. Overexpression of PRMT5 promoted cancer progression, while shRNA knockdown showed an opposite effect. Using an innovative AlphaLISA high throughput screen, we discovered a lead compound, PR5LL-CM01, which exhibited robust tumor inhibition effects in both cancers. An in silico structure prediction suggested that PR5-LL-CM01 inhibits PRMT5 by binding with its active pocket. Importantly, PR5-LL-CM01 showed higher anti-tumor efficacy than the commercial PRMT5 inhibitor, EPZ015666, in both PDAC and CRC. This study clearly highlights the significant potential of PRMT5 as a therapeutic target in PDAC and CRC, and establishes PR5-LL-CM01 as a promising basis for new drug development in the future.
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