Khondaker Miraz Rahman
Transcriptogen Limited, UK
Title: Targeting transcription factors with DNA interactive small molecules
Biography
Biography: Khondaker Miraz Rahman
Abstract
Transcription factors are regulatory macromolecules that induce profound and sustained effects in cells by interacting with, and modulating the expression of genes responsible for critical cellular processes. Interaction of a small molecule with the consensus DNA sequence can prevent a transcription factor from recognizing its cognate sequence, thereby preventing expression of genes associated with the transcription factor. Transcription factor inhibition is an exciting new area of drug discovery, and is considered by some experts to represent the “next wave” of cancer therapeutics following the kinase inhibitors (which have now reached maturity) and the antibody-based approaches which are now in the ascendancy. There are few approved drugs at present that work by selectively inhibiting transcription factors, and so there is significant clinical and commercial potential. From a scientific/clinical perspective, this approach has the advantage that a selective and potent inhibitor would act at the ultimate signalling point of gene expression (i.e., the promoter region of a gene) thus directly modulating the expression of genes carrying the cognate DNA recognition site of the targeted transcription factor. Furthermore, there are sub-families of transcription factors (e.g., STAT1 and STAT3), and it may prove possible to target these independently, thus achieving fine-control over transcription. This is an important distinction from the kinase inhibitors that also modulate gene expression, but have multi-pathway downstream targets and are rarely highly selective, as their kinase target will usually control a range of transcription factors. The talk will explore innovative DNA targeting therapeutic approaches to develop low molecular weight “druggable” molecules that can be targeted to unique transcription factor recognition sites in the human genome. Various mechanisms can be used including the inhibition of protein-protein interactions (PPIs) and protein-DNA interaction (PDIs). A number of duplex-DNA and promoter G- Quadruplex-binding agents are being developed to target the PDI interaction, and some examples will be presented