Musashi-1 (Msi1) is a stem cell marker overexpressed in many types of cancers. Msi1 is an RNA-binding protein (RBP) that binds to and inhibits translation of target mRNAs. This inhibition results in activation of Wnt and Notch signaling and consequently, cell cycle progression, survival, and resistance to programmed cell death. Experimental manipulation to reduce Msi1 levels in breast and colon cancer cell lines leads to tumor regression in mouse xenograft models. Because Msi1 stimulates both Notch and Wnt signaling and is overexpressed in a wide variety of cancers, Msi1 is an attractive target for developing novel cancer therapy. So far there are no reported small molecule inhibitors of the Msi1-RNA interaction. RBPs such as Msi1 are considered "undruggable" due to the lack of a well-defined binding pocket for target RNA. Through high throughput screening, we have obtained initial hits at nanomolar Ki, which are validated by Surface Plasmon Resonance (SPR) and Nuclear Magnetic Resonance (NMR). Our hypothesize that small molecule compounds that disrupt Msi1-RNA binding will block Msi1 function, leading to translation of target genes that are critical for inhibiting cancer cell growth and progression. Our objective is to obtain a series of small molecule compounds as chemical probes that potently bind to Msi1 and modulate its function, and ultimately select 1-2 most drug- like lead compounds for further development as a whole new class of molecular cancer therapy that inhibit cancer with Msi1 overexpression. To test our hypothesis, three Specific Aims will be carried out:
AIM 1, Structure-based rational design and lead optimization of Msi1-inhibitors;
AIM 2, In vitro anti-tumor activity, target validation, and mechanism of action studies;
AIM 3, In vivo efficacy studies of the lead Msi1-inhibitors in xenograft models of human cancer. Overall Impact: Successfully carried out, this project will discover novel chemical probes for Msi1 and potentially lead compounds as Msi1-inhibitors that inhibit cancer cells with high levels of Msi1-Notch/Wnt signaling. Discovery of such Msi1-inhibitors will: (1) provide potent and useful chemical probes for delineating the functional roles of Msi1-Notch/Wnt signaling in cancer initiation and progression;and (2) provide promising lead compounds to develop novel molecular therapeutics targeting the oncoprotein Msi1. The data and leads obtained will enable us to seek out partners for further drug discovery and development studies. After assessing structure-activity relationships 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 inhibitors targeting RNA-binding protein Musashi-1 (Msi1), as new chemical probes and eventually novel molecular cancer therapy that inhibit cancer with Msi1 overexpression. Successfully carried out, the data and leads obtained will enable us to seek out partners for further drug discovery and development studies. After assessing structure-activity relationships 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 #
1R01CA178831-01A1
Application #
8696948
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (58))
Program Officer
Misra, Raj N
Project Start
2014-09-19
Project End
2015-08-31
Budget Start
2014-09-19
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$432,491
Indirect Cost
$140,829
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