Novel Small Molecule Inhibitors of Choline Kinase Identified by Fragment-Based Drug Discovery

Choline kinase α (ChoKα)
is an enzyme involved in the
synthesis of phospholipids and thereby plays key roles in regulation
of cell proliferation, oncogenic transformation, and human carcinogenesis.
Since several inhibitors of ChoKα display antiproliferative
activity in both cellular and animal models, this novel oncogene has
recently gained interest as a promising small molecule target for
cancer therapy. Here we summarize our efforts to further validate
ChoKα as an oncogenic target and explore the activity of novel
small molecule inhibitors of ChoKα. Starting from weakly binding
fragments, we describe a structure based lead discovery approach,
which resulted in novel highly potent inhibitors of ChoKα. In
cancer cell lines, our lead compounds exhibit a dose-dependent decrease
of phosphocholine, inhibition of cell growth, and induction of apoptosis
at low micromolar concentrations. The druglike lead series presented
here is optimizable for improvements in cellular potency, drug target
residence time, and pharmacokinetic parameters. These inhibitors may
be utilized not only to further validate ChoKα as antioncogenic
target but also as novel chemical matter that may lead to antitumor
agents that specifically interfere with cancer cell metabolism.