Table 6. In Vitro and In Vivo Profile of Compound 30a.
| 30: MW = 556/TPSA = 102/log D7.4 = 3.8 | |
|---|---|
| S(10) @ 3 μMb | 0.010 |
| Enz LR IC50 (nM) | 7.4 |
| Enz LR/TM IC50 (nM) | 0.4 |
| Enz LR/TM/CS IC50 (nM) | 0.5 |
| Enz ex19del IC50 (nM) | 25 |
| Enz ex19del/TM IC50 (nM) | 0.8 |
| Enz ex19del/TM/CS IC50 (nM) | 0.7 |
| Enz WT IC50 (nM) | 683 |
| pEGFR PC-9 ex19del IC50 (nM) | 130 |
| pEGFR H1975 LR/TM IC50 (nM) | 1.1 |
| pEGFR A431 WT IC50 (nM) | 544 |
| Ba/F3-EGFR-LR/TM/CS IC50 (nM) | 3.2 |
| Ba/F3-EGFR-ex19del/TM/CS IC50 (nM) | 4.0 |
| thermodynamic solubility at pH 1.5/6.5 (mg/mL) | 11/0.01 |
| plasma protein binding (%fu): human, rat, cyno, dogc | 1.1, 0.9, 3.5, 1.4 |
| rat: Clp (mL min–1 kg–1), t1/2 (h), Vss (L/kg), %Fd | 32.4, 1.3, 2.3, 48% |
| cyno: Clp (mL min–1 kg–1), t1/2 (h), Vss (L/kg), %Fe | 4.9, 3.5, 1.6, 33% |
| dog: Clp (mL min–1 kg–1), t1/2 (h), Vss (L/kg), %Ff | 13.7, 4.9, 3.9, 49% |
Biochemical assays using different EGFR variants measures 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, ex19/TM = ex19del(746–750)/L858R, and ex19/TM/CS = ex19del(746–750)/L858R/C790S. PC-9 is a human lung cancer cell line harboring the EGFR ex19del(746–750) mutation. H1975 is a human lung cancer cell line harboring the EGFR L858R/T790M mutation. A431 is a cell line in which EGFR is amplified. Ba/F3 cells are transduced with lentiviral particles encoding for mutant EGFR.
DiscoverX’s KINOMEscan selectivity profiling at 3 μM, S(10) = (number of non-mutant kinases with %Ctrl < 10)/(number of non-mutant kinases tested).
Plasma–protein binding was determined by an ultracentrifugation method.
Sprague–Dawley rats (n = 3); IV dose = 1 mg/kg using 10% DMSO, 10% solutol, 80% “20% HP-β-CD in water” and PO dose = 2.5 mg/kg, solution of 10% DMSO, 10% solutol, 80% “20% HP-β-CD in water”.
Cynomolgus monkey (n = 3), IV dose = 0.5 and PO dose = 2.5 mpk using formulation vehicle: solution of 5% DMSO + 5% kolliphor HS 15 + 90% saline.
Beagle dogs, IV dose = 0.5 mg/kg using 5% DMSO + 5% kolliphor HS 15 + 90% saline and PO dose = 2.5 mg/kg using suspension of 0.5% (w/v) CMC-Na + 0.1% (v/v) Tween 80 in Milli-Q water.