Figure 5.

Summary of potencies, selectivities and pharmacokinetic properties of compound 27. ^aAll IC₅₀ values are reported as the mean of at least two determinations. ^bInhibition of purified recombinant human GLS-1 (GAC isoform) assessed via a dual-coupled enzyme assay. IC₅₀ value is the mean ± standard deviation for 36 determinations. ^cInhibition of purified recombinant human GLS-2 assessed via a dual-coupled enzyme assay. ^dInhibition of proliferation of A549 cells. IC₅₀ value is the mean ± standard deviation for 36 determinations. ^eInhibition of cellular glutaminase assessed via direct measurement of glutamine and glutamate levels in the cellular media. IC₅₀ value is the mean ± standard deviation for 4 determinations. ^fhERG QPatch assay, CHO cell line. ^gInhibition of metabolism of known substrates for the indicated cytochrome P450 enzymes. ^hEurofins CEREP profiling service; details in the supporting information. ⁱEurofins DiscoverX KINOMEscan profiling service, scanEDGE product; details in the supporting information. ^jLiver microsomal intrinsic clearance (mL/min/kg protein). ^kLiver hepatocyte intrinsic clearance (mL/min/kg protein). ^lPlasma protein binding determined by equilibrium dialysis. ^mDosed as a bis-hydrochloride salt to female CD-1 mice, male Sprague-Dawley rats, male cynomolgus monkeys and male beagle dogs. Doses were 0.3 mg/kg IV (intravenous) and 3 mpk PO (per os), except for mouse (3 mpk IV, 10 mpk PO). C_max, AUC_last and F % were determined from the oral dose and CL, Vd_ss and t_1/2 were determined from the IV dose.