Drug repurposing screen to identify potent inhibitors of CK AML proliferation. (A) Layout of the discovery primary chemical screen. (B) Comparison of JAK1/2 inhibitor ruxolitinib activity in CK JAK2^WT vs JAK2^mut AML specimens. (C) Comparison of MEK1/2 inhibitor trametinib activity in CK RAS^WT vs RAS^alt AML. (D) Overview of the results of the discovery primary chemical screen. Compounds are ordered from the most active (left) to the least active (right) in CK AML. Upper panel shows median IC₅₀ in CK AML; middle panel shows differential sensitivity in CK vs intermediate risk AML, and lower panel shows the statistical significance of these differences. PLK1 inhibitors are shown in red, and other selected compounds are shown in blue. (E) Most active compounds on CK AML are listed with their corresponding IC₅₀ (Log₂ nM) and targets. (F) Volcano plot showing the differential sensitivity in CK vs intermediate risk AML of compounds active in CK AML (IC₅₀ < 1000 nM). Dot plot comparison of rigosertib (G), daunorubicin (H), and cytarabine (I) IC₅₀ values (Log₂ nM) between intermediate risk and CK AML. (J) Volcano plot showing the differential sensitivity in CK TP53^WT vs TP53^alt of compounds active in CK AML (IC₅₀ < 1000 nM). In volcano plots, PLK1 inhibitors rigosertib and volasertib are depicted in red, whereas cytarabine and daunorubicin are depicted in blue. Medians are represented by a black line in dot plots. HDAC, histone deacetylase; nb, number; NS, not significant.