microRNA AND Lin28/Let-7 AXIS
An unexpected discovery to come out of the Human Genome Project is that ninety-eight percent of our genome does not code for proteins. Rather, a significant portion of the genome produces non-coding RNAs (ncRNAs). Intensive research over the past decade has revealed that ncRNAs have critical functions in the regulation of nearly all biological processes.
28-7’s initial focus is on modulating micro RNAs (miRNAs), which are short ncRNAs that inhibit target gene expression by suppressing mRNA translation and/or promoting mRNA decay. It is now well recognized that miRNAs are directly involved in cancer initiation, progression, and metastasis.
28-7’s technology does not focus on directly targeting the RNA itself or on developing oligonucleotides, but rather targets RNA modulating proteins (RMPs), enabling the use of small molecule drug candidates with broader access to cells and tissues. Let-7 is an miRNA that suppresses the translation of oncogenes in cells, and low levels of this miRNA are correlated with greater cancer aggressiveness.
The company’s leading protein target is Lin28, an RMP that reduces the levels of Let-7, and has been shown to be an oncogene, promoting cellular transformation and tumorigenesis. 28-7 is developing first-in-class drugs that inhibit Lin28’s activity and thus raise levels of Let-7 for treatment of various cancers.
DRUG DISCOVERY AT TWENTYEIGHT-SEVEN
Our lead oncology program comprises a multi-pronged approach to increase Let-7 levels in cancer cells. Let-7 was identified by 28-7’s co-founders as a tumor suppressor miRNA, and increasing its levels is expected to reduce tumorigenicity. The protein Lin28 binds a precursor of Let-7 and prevents its maturation to a functional tumor suppressing miRNA. We are focused on identifying compounds that inhibit the binding of Let-7 to Lin28 and thereby increasing the levels of this important tumor suppressor.
PLATFORM AND FUTURE PROJECTS
28-7’s expertise in RNA biochemistry, enzymology, and cell biology, and our growing library of compounds that interfere with protein-RNA binding will be leveraged to create additional programs aimed at RNA binding proteins and processing enzymes that play critical roles in human disease.