Selected Publications
- Silva Júnior, P. E.; Rezende, L. C. D.; Gimenes, J. P.; Maltarollo, V. G.; Dale, J.; Trossini, G. H. G.; Emery, F. S.; Ganesan, A. Synthesis of Two ‘Heteroaromatic Rings of the Future’ for Applications in Medicinal Chemistry. RSC Adv. 2016, 6, 22777-22780.
- Davidson, S. M.; Foote, K.; Kunuthur, S.; Gosain, R.; Tan, N.; Tyser, R.; Zhao, Y. J.; Graeff, R.; Ganesan, A.; Duchen, M. R.; Patel, S.; Yellon, D. M. Inhibition of NAADP Signalling on Reperfusion Protects the Heart by Preventing Lethal Calcium Oscillations via Two-Pore Channel 1 and Opening of the Mitochondrial Permeability Transition Pore. Cardiovasc. Res. 2015, 108, 357-366.
- Hamon, M.; Dickinson, N.; Devineau, A.; Bolien, D.; Tranchant, M.-J.; Taillier, C.; Jabin, I.; Harrowven, D. C.; Whitby, R. J.; Ganesan, A.; Dalla, V. Intra- and Intermolecular Alkylation of N,O-Acetals and π-Activated Alcohols Catalyzed by in Situ Generated Acid. J. Org. Chem. 2014, 79, 1900-1912.
- Tortorici, M.; Borrello, M. T.; Tardugno, M.; Chiarelli, L. R.; Pilotto, S.; Ciossani, G.; Vellore, N. A.; Bailey, S. G.; Cowan, J.; O’Connell, M.; Crabb, S. J.; Packham, G.; Mai, A.; Baron, R.; Ganesan, A.; Mattevi, A. Protein Recognition by Short Peptide Reversible Inhibitors of the Chromatin-Modifying LSD1/CoREST Lysine Demethylase. ACS Chem. Biol. 2013, 8, 1677-1682.
- Benelkebir, H.; Donlevy, A. M.; Packham, G.; Ganesan, A. Total Synthesis and Stereochemical Assignment of Burkholdac B, a Depsipeptide HDAC Inhibitor. Org. Lett. 2011, 13, 6334-6337.
FRIAS Project
Targeting Histone-Modifying Enzymes for Epigenetic Drug Discovery.
Epigenetics is the study of how DNA and histone protein modification affect gene transcription in eukaryotes. The DNA and protein modifications are carried out by writer enzymes. For each modification, an eraser enzyme returns the molecule to its native state. In this project, we will target two key histone-modifying eraser enzymes, histone deacetylases (HDACs) and lysine-specific demethylase I (LSD1). HDAC inhibitors are a well validated epigenetic target for drug discovery with five approvals for cancer chemotherapy. However, there are issues with selectivity as the drugs inhibit several or all eleven of the human HDACs. Our approach is to design isoform-selective HDAC inhibitors and profile them biologically in order to understand the specificity that will be therapeutically valuable. In preliminary results, we have identified HDAC6 selective inhibitors. We will prepare two libraries of compounds based around two scaffolds and these will be evaluated in Freiburg. Concurrently, we will work on the second target, LSD1. We have a series of irreversible LSD1 inhibitors with submicromolar activity in acute myeloid leukaemia cell lines. We will prepare additional compounds in the series to optimize their pharmacodynamic and pharmacokinetic properties. In addition, we will identify scaffolds for reversible LSD1 inhibition through in silico screening. Promising candidates will be synthesized and tested in enzyme and cell-based assays for LSD1 inhibitory activity.