The RNA-binding protein Hu antigen R (HuR) is a member of the embryonic lethal abnormal vision (ELAV) family that binds to adenine- and uridine-rich elements (ARE) located in the 3'- or 5'-untranslated region (UTR) of target mRNAs. HuR is overexpressed in a wide variety of cancer, promotes tumorigenesis by interacting with a subset of oncogenic mRNAs implicated in tumor cell proliferation, survival, angiogenesis, invasion, and metastasis. HuR up-regulates the oncogenic Musashi-1/-2 (Msi1/2) and anti-apoptotic proteins, Bcl-2 and XIAP, via binding to AREs and promoting mRNA stability and translation, thus leading to activation of Wnt/Notch signaling pathways and inhibition of apoptosis. These HuR target genes are also involved in cancer stem cell signaling and drug resistance. These findings suggest that HuR is an attractive target for developing novel cancer therapy. So far there is limited success in small molecules that directly inhibit the HuR-RNA interaction. RNA-binding proteins are considered undruggable due to the lack of a well-defined binding pocket for target RNA. Through high throughput screening, we have obtained hits that inhibit HuR at nM to M Ki values, validated by ALPHA, Surface Plasmon Resonance (SPR) and Nuclear Magnetic Resonance (NMR) assays. We hypothesize that small molecules that directly disrupt the HuR-ARE interaction, or HuR-ARE disruptors, will block HuR function, leading to modulation of target genes that are critical for cancer cell growth and progression. Our objective is to obtain a series of small molecule compounds that potently bind to HuR and modulate its functions, and ultimately select 1-2 most drug-like lead compounds for further development as a new class of molecular cancer therapy that inhibit cancer with HuR overexpression.
Three Specific Aims are proposed:
AIM 1, Structure-based rational design and lead optimization of HuR-ARE disruptors;
AIM 2, In vitro anti-tumor activity, target validation, and mechanism of action (MOA) studies;
AIM 3, In vivo efficacy studies of the lead HuR-ARE disruptors in xenograft models of human cancer, including orthotopic tumor models. Overall Impact: Successfully carried out, this project will discover novel chemical probes for HuR and potentially lead compounds as HuR-ARE disruptors that inhibit cancer cells with high levels of HuR-Notch/Wnt signaling. Discovery of such HuR-ARE disruptors will: (1) provide potent and specific chemical probes for delineating the functional roles of HuR-Msi1-Notch/Wnt signaling in cancer initiation and progression; and (2) provide promising lead compounds to develop novel molecular therapeutics targeting the oncogenic HuR. The data and leads obtained will enable us to seek out partners for further drug discovery and development studies. After assessing structure-activity relationships (SAR) and lead optimization, we may obtain a few lead compounds for further development as a whole new class of molecular cancer therapeutics that inhibit specific protein/RNA interactions required for cancer cell survival and progression.

Public Health Relevance

Our objective is to design and synthesize novel small molecule HuR-ARE disruptors targeting the RNA- binding protein HuR, as new chemical probes and potentially new drugs that inhibit cancer cells with high levels of HuR-Notch/Wnt signaling. Successfully carried out, the data and leads obtained will enable us to seek out partners for further drug discovery and development studies. After the proposed structure-activity-relationships (SAR) analysis and lead optimization, we may obtain a few lead compounds for further development as a whole new class of molecular cancer therapeutics that inhibit specific protein/RNA interactions required for cancer cell survival and progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA191785-01A1
Application #
8964473
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Forry, Suzanne L
Project Start
2015-06-01
Project End
2020-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
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Yu, Jia; Lan, Lan; Lewin, Seth J et al. (2017) Identification of novel small molecule Beclin 1 mimetics activating autophagy. Oncotarget 8:51355-51369
Wu, Xiaoqing; Tang, Wenhua; Marquez, Rebecca T et al. (2016) Overcoming chemo/radio-resistance of pancreatic cancer by inhibiting STAT3 signaling. Oncotarget 7:11708-23
Slone, Samuel; Anthony, Sarah R; Wu, Xiaoqing et al. (2016) Activation of HuR downstream of p38 MAPK promotes cardiomyocyte hypertrophy. Cell Signal 28:1735-41