Table 1. Properties of EGFR Inhibitors 4–6a.
| compound |
|||
|---|---|---|---|
| 4 | 5 | 6 | |
| Enz EGFR LR/TM IC50 (nM) | 290 | 99 | 50 |
| Enz EGFR LR/TM/CS IC50 (nM) | 266 | 105 | 46 |
| Enz EGFR WT IC50 (nM) | >10 000 | >10 000 | >10 000 |
| pEGFR H1975 LR/TM IC50 (nM) | 914 | 420 | 67 |
| pEGFR A431 WT (nM) | >25 000 | >25 000 | >25 000 |
| HLM Clint (μL/min/mg) | 4.0 | 9.1 | 19.0 |
a
Biochemical 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 means EGFR L858R/T790M, and EGFR LR/TM/CS means L858R/T790M/C790S. HLM Clint is the measurement of intrinsic clearance obtained from isolated human liver microsomes. H1975 is a human lung cancer cell line harboring the EGFR L858R/T790M mutation. A431 is a cell line in which EGFR is amplified.