Leukemia Cell Cycle Chemical Profiling Identifies the G2-Phase Leukemia Specific Inhibitor Leusin‑1

Targeting the leukemia
proliferation cycle has been a successful
approach to developing antileukemic therapies. However, drug screening
efforts to identify novel antileukemic agents have been hampered by
the lack of a suitable high-throughput screening platform for suspension
cells that does not rely on flow-cytometry analyses. We report the
development of a novel leukemia cell-based high-throughput chemical
screening platform for the discovery of cell cycle phase specific
inhibitors that utilizes chemical cell cycle profiling. We have used
this approach to analyze the cell cycle response of acute lymphoblastic
leukemia CCRF-CEM cells to each of 181420 druglike compounds. This
approach yielded cell cycle phase specific inhibitors of leukemia
cell proliferation. Further analyses of the top G2-phase and M-phase
inhibitors identified the leukemia specific inhibitor 1 (Leusin-1).
Leusin-1 arrests cells in G2 phase and triggers an apoptotic cell
death. Most importantly, Leusin-1 was more active in acute lymphoblastic
leukemia cells than other types of leukemias, non-blood cancers, or
normal cells and represents a lead molecule for developing antileukemic
drugs.