Current cancer chemotherapy relies heavily on cytotoxic agents, such as the
taxanes and Vinca alkaloids, that interfere with the cellular machinery required for cell
division and divert the cell down a pathway of programmed cell death. These
antimitotic agents, or spindle poisons, target the mitotic spindle by binding to tubulin, a
protein required not only for mitosis but also for structural integrity and proper function
of healthy, terminally differentiated cells. To avoid side effects attributed to this
nonselective mechanism of action, new targets in the mitotic pathway that act only in
dividing cells were sought and a leading candidate to emerge from these efforts was
kinesin spindle protein (KSP or HsEg5). KSP is a molecular motor protein that is
expressed only during mitosis and controls the formation of a functional mitotic spindle.
Inhibition of KSP causes mitotic arrest followed by cell death in malignant cells and
thus has the potential to become a novel chemotherapeutic strategy with the potential
for reduced toxicity. This article summarizes efforts carried out at Merck to discover
potent, selective and water soluble KSP inhibitors that culminated in the discovery of
MK-0731, the second KSP inhibitor to enter clinical trials. Of special focus in this
article is how an HTS lead was optimized in apparently divergent directions, but these
disparate leads converged in the design of compounds that overcame P-glycoprotein
efflux and hERG channel activity, two issues that required considerable optimization
within our program.
Keywords: Kinesin spindle protein (KSP), Eg5, spindle poison, anti-mitotic,
mitotic arrest, targeted chemotherapy, MK-0731, allosteric inhibitors, lead
optimization, p-Glycoprotein efflux, PGP, MDR, IKr potassium channel, hERG
channel, QT prolongation, water solubility, phosphate prodrugs, fluorine, amine
basicity, pKa, xenograft studies, continuous infusion, neutropenia.
