Recently,
we have shown that small molecule dCK inhibitors in combination
with pharmacological perturbations of de novo dNTP biosynthetic pathways
could eliminate acute lymphoblastic leukemia cells in animal models.
However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic
properties. We delineated the sites of the inhibitor for modification,
guided by crystal structures of dCK in complex with the lead compound
and with derivatives. Crystal structure of the complex between dCK
and the racemic mixture of our new lead compound indicated that the <i>R</i>-isomer is responsible for kinase inhibition. This was
corroborated by kinetic analysis of the purified enantiomers, which
showed that the <i>R</i>-isomer has >60-fold higher affinity
than the <i>S</i>-isomer for dCK. This new lead compound
has significantly improved metabolic stability, making it a prime
candidate for dCK-inhibitor based therapies against hematological
malignancies and, potentially, other cancers
