Table 2. Structure–Activity Relationship of Selected Analogs of Compound 6.

^aDiscoverX’s KINOMEscan selectivity profiling at 3 μM, S(10) = (number of non-mutant kinases with %Ctrl < 10)/(number of non-mutant kinases tested).

^bBiochemical assays using different EGFR variants measure inhibition in the presence of 1 mM ATP, and compounds were incubated with enzymes for 10 min before ATP and peptide substrate were added (for more details see Experimental Section). EGFR LR/TM = EGFR L858R/T790M, EGFR LR/TM/CS = L858R/T790M/C790S, and ex19/TM/CS = ex19del(746–750)/L858R/C790S.

^cH1975 is a human lung cancer cell line harboring the EGFR L858R/T790M mutation.

^dA431 is a cell line in which EGFR is amplified.

^eIntrinsic clearance obtained from isolated human liver microsomes.

^fLipE = −log(LRTMCS Enz IC₅₀) – log D (calculated from ACD labs @ pH = 7.4). ND: not determined.