Figure 6. Heatmap of cellular EC50 values for leading clinical therapies (S = Sorafenib, A = AC220, P = Ponatinib, PKC412) and Star 27 against a panel of AML-relevant human- and mouse-derived drug-resistant cell lines.
(A) (adapted from Guo et al., 2007; Kampa-Shittenhelm et al., 2013; Smith et al., 2013). Log10-scale fold resistance between Ba/F3 FLT3 ITD and drug-induced mutations (ITD + KD double mutant) shown via heat map. Point mutations corresponding to each drug-relevant resistance shown. Star 27 maintains potency between FLT3 ITD and resistance mutants comparable to PKC412. Mutations derived independently from both saturating mutagenesis and patient-derived samples [Smith et al., 2012]. Replicates shown are the result of at least two or three attempts, each in triplicate, and error ranges represent the standard error of the mean. (B and C) Crenolanib's effect on p-KIT inhibition and of colony growth in normal BM. (B) Crenolanib inhibits p-KIT in HMC1.1 cells at 12 nM IC50. This level of inhibition translates to downstream kinases, with inhibition of p-AKT (S473) and p-S6 (S235/S236). (C) Crenolanib potently inhibits normal BM colony formation at <63 nM and ca. 63 nM IC50's of CFU and BFU colonies, respectively.