Neuroblastoma RAS (NRAS) is an oncogene that is often deregulated mutated in cancers such as melanoma and Acute Myeloid Leukemia (AML). Mutations in NRAS have been linked to more aggressive tumors and poor prognosis. Inhibition of NRAS protein function in mutant melanomas has thus far been difficult to accomplish. However, some success has been achieved indirectly with MEK inhibitors that target the PI3K-AKT pathway. Growing resistance to these drugs has led to new research in alternative approaches to target NRAS. One such approach is to target a G-quadruplex secondary structure found in the NRASmRNA. Initial work with probe compounds has provided proof of concept, but the need for a more selective inhibitor of NRAS is paramount in the effort to combat aggressive melanomas. In order to find a selective ligand for the NRAS G-quadruplex, we performed a small molecule microarray (SMM) screen. Investigation of a class of compounds identified in this screen led to a compound with a binding affinity of approximately 130 nM to the G-quadruplex. Initial in vitro translation inhibition assays show a dose-dependent reduction in the amount of protein produced from G-quadruplex-containing NRAS transcript. This poster will detail our efforts to study this class of compounds in biochemical, biophysical, and cellular assays to probe modulation of NRAS protein with mRNA-binding small molecules.

Binding and inhibition of NRAS mRNA with drug like small molecules

2019 Spring National Meeting

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