DNA-dependent protein kinase (DNA-PK) is a key enzyme involved in the repair of DNA double strand breaks (DSBs). Compound 401 is a synthetic inhibitor of DNA-PK (IC50 = 0.28 μM) that also targets mTOR (IC50 = 5.3 μM) but not p110α/p85α PI3K in vitro[3]. Compound 401 inhibited mTOR activity in Raptor immunoprecipitates by 67% or 78% at 5 μM or 10 μM, respectively. In serum-starved Rat-1 fibroblast, 401 (10 μM) nearly completely decreased the phosphorylation of both S6K1 Thr389 and Akt Ser473 but with little effect on PI3K activity. In TSC1/cells, proliferation was strongly inhibited when exposed to 401 for 1 day (54%) or 2 days (84%). Growth inhibition by 401 was dose-dependent with a half-maximal effect at roughly 2 μM which is due in part to suppression of mTORC2/Akt signaling[3].
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