DPP8/DPP9 Cancer Immunotherapy

     The dipeptidyl peptidases 8 and 9 (DPP8/9) are two serine proteases that have almost identical binding pockets and that share a very high homology with other members of their family: the dipeptidyl peptidase 4 (DPP4) and the fibroblast activation protein (FAP). The inhibition of these two proteins leads to an up-regulation of the immune system which induces an inflammatory programmed cell death. This up-regulation has also shown to lead to tumor regression and particularly so in acute myeloid leukemia (AML) cell lines as opposed to other type. The therapeutic potential of DPP8/9 is therefore discernible. There are currently few inhibitors that are potent and selective for these proteins because selectivity is difficult to achieve. We focus on the development of highly selective inhibitors for DPP8/9 by implementing new methods in Fitted as to highlight key ligand-receptor interactions. We then synthesize top hits predicted by Fitted and test them in vitro. The compounds that we develop will allow to validate our computational methods in the prediction of selectivity and subsequently allow biologists and biochemists to determine if the therapeutic inhibition of DPP8/9 is an achievable goal, and if this target has potential in the treatment of cancer and acute myeloid leukemia.
Keywords : · Computationally-aided Drug Design · Immunotherapy · Organic synthesis · DPP8/DPP9
Key people involved in the project : Anne Labarre (graduate student)
Key publications related to the project : coming soon!