Professor, Department of Molecular Biosciences
University of Kansas
Fragment-based discovery of chemical probes for RNA-binding protein Musashi-2 (2017-18)
This project relates to the discovery of chemical probes as tools for functional study of a protein critical for cancer initiation and progression. The discovery from this project may be further studied as potential leads for cancer drug discovery, with the ultimate goal of developing the best compound as a whole new class of molecular cancer therapy.
The RNA-binding protein Musashi-2 (MSI2), long considered as a regulator of stem and progenitor cell characteristics, has recently been found to be over-expressed in many types of cancer. MSI2 maintains cancer stem cell populations and regulates cancer invasion, metastasis and development of more aggressive cancer phenotypes, including drug resistance by mediating mRNA stability and translation of proteins operating in essential oncogenic signaling pathways. MSI2 is a promising target for cancer. So far there is limited success on small molecules that directly inhibit MSI2-RNA interaction. RBPs such as MSI2 are considered “undruggable” due to the lack of a well-defined binding pocket for target RNA. We have set up fluorescence polarization (FP) and surface plasmon resonance (SPR) assays for initial screening of a fragment library, and obtained one class of promising MSI2 fragments. However, to make active conjugates, more classes of fragments binding to different sites of the MSI2 RNA-binding pocket are needed. We propose, in the current pilot project, to further screen a larger fragment library to obtain more chemically diverse fragment hits, for subsequent conjugation of active fragments. Our hypothesis for the overall project is that small molecule compounds that disrupt MSI2-RNA binding will block the MSI2 function, leading to translation of target genes that are critical for inhibiting cancer cell growth and progression. Two Specific Aims are proposed: Aim 1, STD-NMR screening of fragment libraries; Aim 2, Validation of hit fragments with binding assays and their anti-tumor activity in cancer cells and target validation.
The success of this one year pilot project will provide us with strong preliminary data and materials enabling us to apply for NIH grants to make chemical conjugates, with structure-based rational design (Docking with NMR/ crystallography data). Our long-term objective is to discover potent and specific chemical probes for delineating the functional roles of MSI2 in cancer initiation and progression, and provide promising hit compounds to further development as novel molecular therapeutics targeting the oncogenic MSI2 protein.