The Flaherty lab pursues a multi-disciplinary approach toward developing small molecule modulators for under-explored and novel targets of therapeutic interest. The primary discipline of our lab is medicinal chemistry/organic synthesis of small molecules. Additionally, members perform biochemical and biophysical assays to assess the binding characteristics of molecules to inform further design.
Drug repurposing to combat vancomycin-resistant enterococcus and Neisseria gonorrhoeae
In collaboration with Dr. Mohamed Seleem (Virginia Tech University) we have discovered and developed potent and highly selective anti-VRE molecules based on the scaffold of an existing FDA approved drug. These molecules show efficacy in in vivo models to treat VRE infections. The intracellular target for these molecules is also previously uncharacterized making it a novel anti-VRE therapeutic target. The project was recently funded by the NIH and will be progressing toward advancing molecules to human studies.
Inhibitors of vancomycin-resistant enterococcus in J Med Chem
In vivo efficacy of acetozolamide versus enterococcus
Inhibitors of Neisseria gonorrhoeae carbonic anhydrase
Efficacy of dorzolamide in treatment of enterococcus
Anion inhibition studies against Neisseria gonorrhoeae carbonic anhydrase
Crystal structure of inhibitors bound to Neisseria gonorrhoeae carbonic anhydrase
Small molecule modulators of UCHL1
Deubiquitinating enzymes have become increasingly popular drug targets for a variety of indications. This class of enzyme is heavily involved in signaling pathways to turn on/off processes, control cellular trafficking, and sending proteins to degradation through the ubiquitin-proteasome system. Our lab is currently pursuing best-in-class inhibitors versus Ubiquitin C-terminal hydrolase L1 (UCHL1). UCHL1 expression correlates well with tumor size and invasiveness and further studies have shown that it appears to regulate pathways leading to metastasis. Our team is using a traditional and fragment-based approaches to discover covalent small molecule inhibitors with therapeutic potential to treating aggressive forms of cancer. Our group is also leveraging ubiquitin as a scaffold to design UCHL1 selective ubiquitin variants. These variants will be able to be applied to modulate or track UCHL1 activity in cells.
Characterization of cyanopyrrolidine-based covalent inhibitor
Development of ubiquitin variants with selectivity for ubiquitin C-terminal hydrolase deubiquitinases
Fluoromethylketone covalent UCHL1 inhibitors
Inhibitors of adenylyl cyclase type 1
This project is a interdisciplinary collaboration involving four labs within MCMP. Dr. Watts lab has extensive expertise studying the pharmacology of adenylyl cyclases (AC) and has shown that AC1 is a potential target to treat inflammatory pain. This team has embarked upon as small molecule AC1 inhibitor campaign in which the Flaherty lab provides medicinal chemistry support and coordinates with the lab of Dr. Markus Lill for analog design based on computational models. Analogs to the Watts lab for testing and any prioritized molecules move to in vivo studies in Dr. Van Rijn's lab. This project embodies the benefits of housing both medicinal chemistry and pharmacology expertise in the same department. *Data image borrowed from Brust et al, Sci Signal, 2017, 10, eaah5381
1,3,4-oxadiazole AC1 inhibitors
Pyrimidinone-based inhibitors of adenylyl cyclase type 1 for treatment of chronic pain
Inhibitors of S. aureus RnpA
Ribonuclease P (RNAse P) is a ribozyme that has long been known to process pre-tRNA in bacteria species via cleavage of the 5' leader sequence. However, recent studies have shown that the protein subunit, RnpA, also has a role in mRNA degradation. Previous efforts to develop inhibitors for RnpA have focused on it's role in as a substrate binding domain in the ribozyme. We are tackling this problem from a different point of view and searching for molecules that are dual functional. Using both traditional and fragment-based screening approaches our lab is developing molecules that can inhibit one or both of these RNA metabolism processes as a means to validate targeting the RnpA subunit for small molecule drug discovery.
S. aureus RnpA crystal structure
Novel small molecule inhibitors of RnpA