The main focus of the Tavassoli lab has been the establishment and utilization of a genetically encoded high-throughput screening platform for the identification of protein-protein interaction inhibitors. our goal is the development of compounds capable of disrupting the association and assembly of protein complexes. A key area of interest for the lab is uncovering compounds that disrupt metabolite-sensing transcription factors. The compounds uncovered in our lab serve as valuable tools that allow better understanding of the link between tumour metabolism and the altered gene expression of cancer cells. These compounds also form the starting point for the development of therapeutic compounds that target key protein-protein interactions in disease. Our research group is focused on training scientists at the chemistry-biology interface, and using these interdisciplinary skills to help understand the fundamentals of cell biology and to develop new therapeutic agents.
Some of the projects currently underway in the lab are highlighted below.
The first specific inhibitor of HIF-1α/HIF-1β protein-protein interaction
HIF-1 is the cellular sensor of oxygen, and a key protein in the adaptation and survival of cancer cells in the hypoxic tumour microenvironment. We have recently reported the first specific inhibitor of HIF1α/HIF-1β dimerization. The inhibitor was identified using our bacterial high-throughput screening platform, and was extensively characterized in vitro and in cells, and shown to inhibit hypoxia-response signaling in cells. We also demonstrated that the compound does not disrupt the dimerization of HIF-2α/HIF-1β in vitro and in cells.
This work has generated significant media interest, including the CRUK blog.
This work is funded by Cancer Research UK.
The first example of a non-natural, biocompatible DNA-backbone linker (with Prof. Tom Brown)
Current DNA synthesis methods do not allow the preparation of epigenetically modified DNA fragments larger than ~200 bases (methods such as PCR use enzymes that can not read epigenetic information, and so any epigenetic information incorporated at the oligonucleotide synthesis stage will be erased in the amplified, assembled DNA). We are therefore seeking to establish a chemical method for DNA ligation that would allow assembly of synthetic oligonucleotides by a purely chemical method. This would allow the synthesis of large oligonucleotides (genes and genomes) that contain epigenetic information, and provide a significant tool for the study of epigenetics.
A key requirement for the above is the biocompatibility of the resulting non-natural DNA linker in living systems. We have assesses the suitability of click-linked DNA for this purpose; modified bases were incorporated at the appropriate termini of oligonucleotides, and linked by click chemistry. We have recently shown that the resulting non-natural triazole linked (replacing the phosphodiester normally present in DNA) is fully biocompatible in E. coli and mammalian cells.
This work is funded by the BBSRC and EPSRC.
The first inhibitor of CtBP homodimerization (with Dr. Jeremy Blaydes)
C-termina binding proteins are transcriptional regulators that dimerize in response to increased NADH levels, and modulate the gene expression. We used our high-throughput screening platform to identify cyclic peptide inhibitors of CtBP dimerization, and used these sompounds to show metabolic regulation of cell cycle fidelity in cancer cells. Our paper was featured on the cover of the journal Chemical Science.
This work is funded by Cancer Research UK and Breast Cancer Campaign.