Drs. Shuster and Arterbern Develop Novel Compounds for Cancer Research
A collaborative effort between the
laboratories of Drs. Charles Shuster
in the Department of Biology and
Jeffrey Arterburn in Chemistry and
Biochemistry has developed a set of
novel probes for cancer research
and detection. In a project funded
by an Interdisciplinary Research
Grant through the VPR's office, Drs.
Shuster and Arterburn have generated
analogs of S-trityl-L-cysteine
(STLC), a small molecule inhibitor of
the molecular motor Eg5. Eg5 is
critical for proper assembly of the
mitotic spindle in dividing cells, and
inhibition of this motor results in
mitotic arrest and ultimately cell
death. Drugs that target the mitotic
spindle have been used for decades
as the last resort for many aggressive
cancers, but because these
drugs also affect non-dividing cells,
patients commonly suffer severe
side effects such as neuropathy.
Because Eg5 is only expressed in
dividing cells, cancer drugs that
selectively inhibit Eg5 may exhibit
fewer side effects.
Using the parent molecule as a
substrate, the Arterburn lab synthesized
a series of analogs of STLC,
systematically modifying each functional
group in the hopes of altering
the molecules' solubility, membrane
permeability, and inhibitory
activity. Those analogs were then
submitted to three levels of analysis
in the Shuster lab. Using a biochemical
assay, the Shuster lab
analyzed the inhibitory activity of
the analogs using purified Eg5 motor domain, and in parallel, measured
their effects on spindle formation
in cultured tumor cells. As
a last level of analysis, the lab has
started to test whether these compounds
are effective in invertebrate
cells. Since the majority of
basic research on cell division is
done in non-mammalian systems,
it is important to find drugs for
those investigators using insect
or nematode model systems, and
the lab is currently performing
such a screen in Drosophila S2
cells.
From these efforts, the team has found that STLC
analogs with extensive modification of the carboxyl
group retain inhibitory activity and membrane
permeability. These results lay a foundation for the
development of new agents that label Eg5 in living
cells or identify rapidly dividing cells (such as tumors)
in whole animal. Intravital imaging of tumors is
currently performed using an indirect marker for cell
division, and given that Eg5 is only expressed in
dividing cells, Drs. Arterburn and Shuster hope to use
these molecules to generate imaging probes that
unambiguously mark dividing cells in whole animals
or patients.