The primary research goals of the Fletcher Laboratory are the modulation of aberrant protein-protein interactions via (a) novel, small molecule-based recognition strategies in order to develop new therapeutics to treat human diseases, including cancer and inflammation, and (b) state-of-the-art protein degraders that hijack the cell’s protein garbage disposal mechanism.
1. Resisting resistance to FDA-approved anti-cancer drugs
De novo drug design can take over a decade from the bench to the clinic. We are using computer-aided drug design to assist in the re-styling of FDA-approved anti-cancer drugs to equip them with the ability to tackle proven resistance mechanisms.
2. Towards novel therapeutics for cancer and inflammation
2a. Developing first-in-class inhibitors of RNP A18, previously discovered by our collaborator Dr. France Carrier (UM School of Medicine), which is a key regulator of several cellular pathways controlling cancer growth and immune protection
2b. Protein-protein interaction inhibitors of ERK and p38 MAP kinases – cancer, inflammation
This project is in collaboration with Drs. Paul Shapiro and Alex MacKerell, Jr.
3. Targeted Protein Degradation
Mis-folded proteins and protein homeostasis are handled by the ubiquitin-proteasome destruction process within the cell, wherein an E3 ligase facilitates the transfer of ubiquitin onto the target protein, which the proteasome recognizes as a degradation tag. A state-of-the-art strategy towards next-generation therapeutics – termed proteoylsis-targeting chimera (or PROTACs) involves the hijacking of the UPS system to accomplish the targeted destruction of pathogenic proteins. Specific advantages of this strategy over regular small-molecule drugs include: 1. a catalytic mechanism of action; 2. PROTACS are often effective against resistant mutations. PROTACs comprise a ligand for the protein of interest coupled to a ligand for an E3 ligase ligand via various linkers. A potential caveat, then, of PROTAC therapy is their higher molecular weights. We are investigating the development of molecular glues, which may be thought of as a simpler PROTAC in which there is essentially only one ligand that is recognized by both the POI and an E3 ligase, and there is no linker. Accordingly, glues have much lower molecular weights. Currently, there are no rational strategies by which to design molecular glues. Furthermore, there are hundreds of different E3 ligases that remain undrugged. We are harnessing covalent chemistries by installing electrophilic warheads into solvent-exposed domains of ligands for a POI – currently several targets in acute myeloid leukemia (e.g. BCL-2, Aurora Kinases and menin) – such that the warhead may react with an E3 ligase, effectively “gluing” the POI and ligase together, and protein degradation ensues.