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Bluedot Bio is determined to stop cancer maintenance and progression by targeting transcription. Dysregulated transcription is critical for many diseases, including cancer. Although transcription factors are well-studied, attempts to modulate their function have not been successful, classifying transcription factors as previously “undruggable” targets.
Now, with Bluedot Bio’s proprietary new technology, we are driving the development of a new class of drugs that can effectively inhibit the transcription of dysregulated genes.
“If we have this capacity to target transcription factors and inhibit their ability to induce expression of genes, then we have the ability to modulate disease progression”
– Daniel Johnson, PhD – BB1001 Co-Inventor
Transcription is the fundamental biological process that converts genetic information from DNA into RNA into protein. Transcription is also the first step in gene expression. This process is regulated by a series of proteins, including transcription factors. The human genome has hundreds of specialized transcription factors that each regulate the expression of different genes.
Once a transcription factor binds to its specific DNA sequence, it recruits RNA polymerase complex, which synthesizes RNA from the DNA template.
Normally, transcription factors only bind when specific genes need to be expressed, but when transcription factors are dysregulated, it results in the overexpression of genes that can promote diseases such as cancer.
STAT3 is a well-known oncogene that regulates the transcription of several cancer genes. It has been implicated in several tumor types such as head and neck cancer, lung cancer, and colorectal cancer, among others. Modulating overexpressed STAT3 is expected to reduce transcription of the target genes, resulting in tumor cell death.
Previous small molecule inhibitors of STAT3 have shown efficacy in cell and animal models but have had limited success in humans, until the development of the STAT3 cyclic decoy.
The IL-6/JAK/STAT3 signaling pathway creates a cascade effect that results in the activation of genes known for being involved in processes such as a cell’s inflammatory response, cell division, cell death, and tumor growth. The process begins when a ligand, such as IL-6, binds to the cell surface receptor, allowing JAK to add phosphate to the receptor.
Subsequently, STAT3 phosphorylates and dimerizes, allowing it to relocate from the cell’s cytoplasm to the nucleus. Once in the nucleus, phosphorylated STAT3 can bind to the DNA upstream of several key cancer genes and begin transcription.
BB1001 is a first-in-class cyclic oligonucleotide “decoy” molecule that specifically and avidly binds to activated STAT3. BB1001 competitively inhibits STAT3’s ability to bind to DNA and therefore prevents transcription of cancer-promoting genes. BB1001’s mechanism of action results in a therapeutic effect that hinders the progression of cancer.
When phosphorylated STAT3 enters the nucleus, their binds to specific regions of DNA to begin transcription of key cancer genes.
However, BB1001 binds to activated STAT3, preventing it to bind to its cognate cell DNA. Without STAT3 binding the transcription of target genes is inhibited.