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. 2021 Oct 19;2(10):100422. doi: 10.1016/j.xcrm.2021.100422

Figure 2.

Figure 2

EC2319 linker metabolism and species differences

(A) EC2319 has two predicted cleavage sites that allow formation of two active metabolites: the AMT adduct (via disulfide reduction) and the AMT parent drug (via enzymatic cleavage).

(B) Whole-blood stability of EC2319 (500 nM) spiked into EDTA-anticoagulated whole blood (rat/dog/human) and incubated for 30 and 60 min at 37°C. Plasma samples were extracted for LC-MS/MS quantitation of the intact molecule, AMT, and the AMT adduct.

(C) Formation of AMT after 1-h incubation at 37°C in 10% liver cytosols (rat/dog/human) that were pH adjusted to 4.5 or 7.4 and spiked with EC2319 (1 μM).

(D) GGH metabolism of EC2319 (L-cysteine methyl ester linker) compared against three synthetic analogs of alternative linkers (L-cysteine, cysteamine, or L-lysine). After 2-h incubation at 37°C, any AMT formed after enzymatic cleavage was quantified. All values represent the mean ± SD (n = 2).