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

Abstract

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.

A cell-based high-throughput screen identifies tyrphostin AG 879 as an inhibitor of animal cell phospholipid and fatty acid biosynthesis

“…Propanolol has also been shown to inhibit phospholipid biosynthesis in the range of 50–200 μM [ 9 ]. Inhibitors of phosphatidylcholine biosynthesis have been identified and are effective in inhibiting cancer cell growth in culture [ 7 , 8 , 17 , 18 ].…”

Library Design Strategies To Accelerate Fragment‐Based Drug Discovery

“…This library has subsequently been employed in drug-discovery campaigns against ar ange of targets,i ncluding proteasesa nd kinases. [32][33][34] Recently, Clausena nd co-workersp ublished the synthesis and 19 FNMR spectroscopic screening of their fluorinated Fsp 3rich fragment (3F) library;t his was the first example of as ynthetic library fully designed for this purpose (Figure 2). [35] With ah igh degree of three-dimensionality,t he 3F library was designed to address the need to improve the limited shape diversity of many fragment collections, while enabling efficient screening by 19 FNMR spectroscopy.F urthermore, the library also exhibitedo ther desirable properties compared with those of commercial collections, including al ow average Alog P of 0.8 to ensure sufficient aqueous solubility.…”

Molecular structure and differential function of choline kinases CHKα and CHKβ in musculoskeletal system and cancer

“…Understanding the role of CHKβ in bone loss may lead to the discovery of a new molecular target for anti-resorptive drug development. Other small molecule inhibitors to CHKα are also currently being validated for their antioncogenic properties [47]. Despite the extensive evidence suggesting an important role for CHKα in promoting tumour formation, CHKβ has not been implicated in this process.…”