C-Myc translation inhibitors
c-Myc (Myc) is an oncoprotein which is considered one of the most attractive cancer targets given that it is upregulated in most tumors (epithelial, hematopoietic, central nervous system). The inhibition of Myc has been shown to reduce tumor growth and/or survival but after decades of failures to directly target this protein, C-Myc remains an “undruggable” target.
Status
- A novel approach to target the undruggable Myc oncogene in Cancer – reducing Myc protein translation. Compounds were identified which markedly reduced Myc protein levels in lung tumor cell line
- We follow c-Myc translation by using singular pairs of labeled tRNAser and tRNAgln isoforms. This pair is unique to c-Myc mRNA over the mRNA repertoire in target cells, and is therefore its “signature” pair
- A diverse library of 100,000 compounds was screened, generating a set of 20 million images. The resulting big data was analyzed in our cloud-based platform using proprietary image analysis and machine learning algorithms identifying “hits”, compounds that are actively inhibiting the production of c-Myc but do not affect general protein synthesis
- Hits were validated to reduce Myc protein accumulation in tumor cell nuclei as shown by Immunofluorescence against c-Myc
1. PSM Screen: Target-specific tRNA pair
2.3 million images generated per screen
Automatic generation of a clean FRET image
2. High content, cloud-based image analysis
Data generated for 54 million cells
90 different features
Total of 5 billion data points
3. Hit Identification: Big data analysis
4. C-Myc translation inhibitors
c-Myc protein translation in lung cancer cells was monitored using a Myc-selective pair of labeled tRNAs (upper panel). PSM signal is depicted as cyan spots around cell nucleus (blue color). The first panel on the left shows control cells. In each of the next three panels, cells were incubated for 4 hours with different hit compounds from a 100K screen. In the lower panel, levels of Myc protein in cell nucleus is shown (yellow color). In compound-treated wells (4 hours incubation), myc levels are reduced (nuclear membrane is indicated by a solid yellow line around the nucleus).