Such effects have been observed in less-selective inhibitors such as beloranib and BIA 10-2474. Greater levels of liver toxicities and black-box warnings of severe side effects have been noted for reversible kinase covalent inhibitors than for the corresponding irreversible kinase covalent inhibitors. Reversible covalent inhibitors do not have the possibility of irreversible offtarget modification, but (depending on binding constant) the concentrations of inhibitor needed to deactivate protein may be higher, reducing some of the advantages covalent inhibitor. Covalent inhibitors are subject to resistance, however, through mutation of the targeted residues. Since covalent inhibitors tend to target non conserved amino acid residues of target proteins, mutants of the target protein eliding those residues can still function effectively but will be resistant to covalent inhibitors. Finally, accurate kinetic evaluation of covalent inhibitors is more difficult than for reversible inhibitors; while IC50 values (the concentrations of inhibitor at which half of the enzyme activity is inhibited) can be useful measures of reversible inhibition, covalent inhibition may require both the binding of inhibitor to the target protein and the rate of covalent modification to be determined. The desired Kinact/KI value can be obtained from the more simply determined fixed time point IC50 value for covalent inhibitor analysis if the order of addition of compounds is controlled. How can we find covalent inhibitors?