Indiana University-Purdue University Indianapolis (IUPUI) / Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC)
are among the most commonly diagnosed forms of cancer in the United States.
Due to their widespread prevalence and high mortality rate, it is vital to develop
effective therapeutic drugs to combat these deadly diseases. In both PDAC and
CRC, the multifunctional factor nuclear factor kappa B (NF-kB), a central
coordinator of cellular immune responses, is activated abnormally, leading to
tumorigenesis and cancer progression. Therefore, controlling NF-kB activity is
critical in the treatment of these cancers. In a previous study, we identified a new
mechanism by which NF-kB activity is regulated by an epigenetic enzyme known
as protein arginine methyltransferase 5 (PRMT5). We showed that
overexpression of PRMT5 not only activated NF-kB, but also significantly
promoted several characteristics associated with cancer, including increased cell
proliferation, migration, and anchorage-independent growth in both PDAC and
CRC cells. Moreover, in order to examine the therapeutic potential of PRMT5 in
these cancers, we adapted the state-of-the-art AlphaLISA technique into a high
throughput screen (HTS) platform to screen for PRMT5 inhibitors. As a result, we
successfully identified the small molecule PR5-LL-CM01 as our lead hit. Further
validation experiments confirmed that PR5-LL-CM01 is a potent and specific
PRMT5 inhibitor that exhibits significant anti-tumor efficacy in both in vitro and in
vivo models of PDAC and CRC. Additionally, in a second screen, we discovered two natural compounds, P1608K04 and P1618J22, that can also function as the
PRMT5 inhibitors. These findings further highlight the robustness of the PRMT5-
specific AlphaLISA HTS technique. To conclude, we describe here for the first
time a novel role of PRMT5 as a tumor-promoting factor in PDAC and CRC
through NF-kB activation. By successfully developing and applying an innovative
AlphaLISA HTS technique, we discovered PR5-LL-CM01, P1608K04, and
P1618J22 as novel PRMT5 inhibitors, with PR5-LL-CM01 showing the strongest
potency in both PDAC and CRC models. Therefore, we demonstrated that
PRMT5 is a promising therapeutic target in PDAC and CRC, and the novel
PRMT5 inhibitor PR5-LL-CM01 could serve as a promising basis for new drug
development in PDAC and CRC.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/18096 |
| Date | 12 1900 |
| Creators | Prabhu, Lakshmi Milind |
| Contributors | Lu, Tao, Safa, Ahmad, Pollok, Karen, Skaar, Todd, Zhang, Jian-Ting |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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