Page 30 - I. Chemical biology and drug discovery

[I. Chemical biology and drug discovery-16]

Exploration of anticancer agents showing chemical synthetic

lethal interaction with CaMKII inhibitors in glioblastoma

stem-like cells

Jang Mi Han¹, Hye Jin Jung¹˙*

¹Pharmaceutical Engineering & Biotechnology, Sun Moon University, Asan 31460, Korea

Glioblastoma stem cells (GSCs) drive tumor initiation, cancer invasion, immune evasion, and therapeutic resistance,
and are thus a key therapeutic target for improving glioblastoma multiforme treatment. We previously identified
Ca2+/calmodulin-dependent protein kinase II (CaMKII) as a novel molecular target to eliminate GSCs. In this study,

we aimed to explore the anticancer agents that act synergistically through synthetic lethal interaction with CaMKII
inhibitors in GSCs. The high-throughput drug combination screening based on luminescent cell viability assay was

performed using CaMKII inhibitors (berbamine, HBC) and 1280 compounds, covering a range of pharmacological
targets. As a result, four different compounds (77, 521, 867, 1051) showed significant synthetic lethal interactions

with berbamine or HBC in U87MG-derived GSCs. Combination of CaMKII inhibitors and the compounds markedly
reduced the viability, neurosphere formation, and migration of GSCs compared to each compound alone. The

synthetic lethal interactions were further validated using another CaMKII inhibitor KN93 and U373MG-derived GSCs.
Therefore, the chemical synthetic lethality screen may provide novel potential anticancer agents and interactive

biomolecules to reinforce CaMKII-targeted therapy of GSCs.