Our Science and Pipeline
microRNA AND LIN28/LET-7 AXIS
A startling discovery to come out of the Human Genome Project is that ninety-eight percent of our genome does not code for proteins, rather, much of it produces non-coding RNA. Intensive research over the past decade has revealed that ncRNAs have critical roles in the regulation of nearly all biological processes.
One category of ncRNA that is of initial interest to Twentyeight-Seven is microRNA. miRNAs are short ncRNAs that inhibit target gene expression, and play causative roles in cancer. The miRNA let-7 is a tumor suppressor that inhibits expression of key oncogenes, and is down-regulated in many different cancer types.
let-7 is generated by a process that involves the initial cleavage of its primary miRNA transcript (pri-let-7) to generate pre-let-7, followed by processing of pre-let-7 into mature let-7. In cancer cells, the biogenesis of let-7 is blocked by LIN28A and LIN28B, RNA-binding proteins that have been shown to be oncogenes.
LIN28B acts in the nucleus to sequester pri-let-7 and prevent its further processing, while LIN28A acts in the cytoplasm to present pre-let-7 to Zcchc11, a 3’-terminal uridyltransferase (TUTase) that poly-uridylates pre-let-7. poly-uridylated pre-let-7 is then degraded by an exonuclease.
DRUG DISCOVERY AT TWENTYEIGHT-SEVEN
Our first oncology program comprises a multi-pronged approach to increase let-7 levels in cancer cells. We will first focus on the identification of LIN28A antagonists and Zcchc11 inhibitors, and then follow-on with the identification of LIN28B antagonists.
LIN28A Antagonists We have developed a biochemical assay that measures the association of LIN28A and pre-let-7. This assay was used to screen a large, proprietary library of drug-like molecules. A number of compounds were identified in this screen, thus demonstrating the feasibility of antagonizing the interaction between LIN28A and pre-let-7 with a small molecule. These compounds were carefully evaluated to confirm MOA and have become the basis of a medicinal chemistry program.
Zcchc11/TUTase Inhibitors We also developed a proprietary enzymatic assay to measure the LIN28A-dependent poly-uridylation of pre-let-7 by Zcchc11. There is little information in the literature characterizing this novel class of enzymes, or precise assays for its activity. A high-throughput screen was run using this assay. Several inhibitors were identified and are now being evaluated.
LIN28B Antagonists The starting point for this program is the collection of LIN28A antagonists that were identified in the HTS. Several of these molecules have now been shown to antagonize LIN28B.
PLATFORM AND FUTURE PROJECTS
Twentyeight-Seven’s expertise in RNA biochemistry, enzymology, and cell biology, and our growing library of LIN28A antagonists and TUTase inhibitors will be leveraged to create additional programs aimed at RNA binding proteins and processing enzymes that play critical roles in human disease.