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Metals and ABPP
Transition metals like copper and zinc have important roles as cofactors for various enzymes. There is increasing evidence that changes in metal levels may drive cancer and other diseases. Progress in chemical biology and activity-based protein profiling (ABPP), a method to determine the protein targets of various probes, has created better tools to study the role of metals in disease. With the Chris Chang Lab at UC Berkeley and Brady Lab at Penn as the key research groups. And with in vitro data currently implicating metals in cancer and neuro, there is a need to systematically map out protein/metal binding sites and understand if they can/should be drugged.
Copper (Cu) represents the immediate value of mapping metal binding sites. The metal plays a dynamic role in cellular growth:
Copper-dependent phosphodiesterase 3B (PDE3B) in lipolysis
Mitogen-activated protein kinase kinase 1 (MEK1) and MEK2 in cell growth and proliferation
ULK1 and ULK2 (kinases) in autophagy
Used as a redox agent, copper can play a role in enzyme function and activate certain pathways. But beyond approximately 10 μM, the metal helps produce reactive oxygen species leading to toxicity. From the Brady Lab, past work has established Cu’s ability to activate the MAPK pathway (important for cancer growth) through the MEK1/2 kinases. There might be an opportunity to develop a drug candidate that disrupts Cu/MEK binding to treat cancer. Follow-up work has been done here but there are major in vivo hurdles (i.e. measuring Cu) especially around verifying the MoA is relevant in animal models. This is due to metal complexes being much more susceptible to hydrolysis than organic ones.
Broadly the field of metalloallostery is pretty wide open. There are particular commercial opportunities with kinases and using a Blueprint Medicines development strategy once a metal/kinase target can be validated in vivo. Then the mechanisms by which copper and other metals affect signaling pathways and enzyme activities are not really defined. So on the platform side, there is a need to map out copper-dependent signaling across cancer using ABPP.
Pointing ABPP toward metals has the potential to produce first-in-class medicines in cancer and probably neuro as well. Given that various metal binding sites are not well annotated in the genome, at least 1% of all proteins can bind Cu, there are probably new MoAs to be uncovered for undrugged targets. Focusing on kinases will have the largest impact right now given their role in cancer and the clinical success of the target class.
There is also an interesting idea to build an inorganic chemistry platform that accounts for the different coordinates and valence states of metals interacting with the kinome. Due to their diversified geometries, coordination numbers, and redox states, metals might be more amenable to rational drug design with predictable pharmacokinetic and pharmacodynamic properties. That’s a big if though. But the longshot thought here is that differential valence states and other features could generate a spectrum of pharmacological activities. This could make developing pro-drugs easier and more precisely affect deactivation levels.