Table 5 Multitarget inhibitors
From: Emerging strategies to overcome resistance to third-generation EGFR inhibitors
Number | Target | Pharmacophores | Structure | Activity |
|---|---|---|---|---|
69 [168] | EGFR/FGFR1 | Pyrimidine-2,4-diamines |
| EGFRL858R/T790M IC50 = 43.1 nmol/L EGFRWT IC50 = 1138.7 nmol/L FGFR1WT IC50 = 17.6 nmol/L H1975 cells IC50 = 336.3 nmol/L |
70 [169] | EGFR/Src | Pyrimidine-4-amines |
| K562 cells IC50 = 220 nmol/L A549 cells IC50 = 250 nmol/L EGFR inhibition rate = 33.15% (10 µmol/L) Src inhibition rate = 72.12% (1 µmol/L) |
71 [170] | EGFR/HER4 | 3-Cyanoquizolines |
| EGFRL858R IC50 = 419 nmol/L EGFRWT IC50 = 2.4 nmol/L HER4 IC50 = 0.03 nmol/L |
72 [171] | EGFR/COX2 | 1,3,4-Oxadiazole scaffold |
| EGFR IC50 = 280 nmol/L COX2 IC50 = 170 nmol/L UO-31 cells IC50 = 5800 nmol/L |
73 [172] | EGFR/BRAF | Spirobenzo[h]chromene derivatives |
| EGFR IC50 = 1200 nmol/L BRAF IC50 = 2600 nmol/L A549 cells IC50 = 1780 nmol/L MCF-7 cells IC50 = 4090 nmol/L HT-29 cells IC50 = 4450 nmol/L |
74 [173] | EGFRT790M/ALK | Pyrimidine-2,4-diamines |
| ALK IC50 = 18 nmol/L EGFRWT IC50 = 151 nmol/L EGFRT790M IC50 = 2 nmol/L EGFRL858R/T790M IC50 = 4 nmol/L DFCI032 cells IC50 = 170 nmol/L DFCI076 cells IC50 = 820 nmol/L |
75 [174] | EGFRWT and mutant EGFR/ALK | Pyrimidine-2,4-diamines |
| EGFRWT IC50 = 108 nmol/L EGFRT790M IC50 = 3.9 nmol/L EGFRL858R/T790M IC50 = 3.6 nmol/L ALKWT IC50 = 9.8 nmol/L ALKR1275Q IC50 = 0.82 nmol/L ALKL1196M IC50 = 0.59 nmol/L ALKF1174L IC50 = 0.92 nmol/L ALKC1156Y IC50 = 1.0 nmol/L H1975 cells GI50 = 15 nmol/L H3112 cells GI50 < 0.3 nmol/L |
76 [175] | EGFR/ATX | Pyrimidine-4-amines |
| EGFR IC50 = 24.2 nmol/L ATX IC50 = 29.1 nmol/L A549 cells IC50 = 4960 nmol/L MKN-45 cells IC50 = 3430 nmol/L SGC cells IC50 = 2910 nmol/L CFs cells IC50 = 1490 nmol/L |
77 [176] | EGFR/AURK A | Pyrimidine-4-amines |
| AURK A IC50 = 1990 nmol/L EGFR IC50 = 3.76 nmol/L |
78 [177] | EGFR/IGF1R | Pyrimidine-2-amines |
| EGFR IC50 = 35.5 nmol/L EGFRT790M IC50 = 66.0 nmol/L IGF1R IC50 = 52.0 nmol/L |
79 [178] | EGFR/tubulin | Pyrimidine-4-amines |
| EGFR IC50 = 30 nmol/L Tubulin assembly IC50 = 710 nmol/L HeLa cells IC50 = 1 nmol/L HT-29 cells IC50 = 20 nmol/L Jurkat cells IC50 = 1 nmol/L RS4;11 cells IC50 = 1 nmol/L |
80 [179] | EGFR/tubulin | Chalcones |
| EGFR IC50 = 39 nmol/L Tubulin polymerization IC50 = 8840 nmol/L MCF-7 cells IC50 = 1650 nmol/L HCT-116 cells IC50 = 3610 nmol/L |
81 [180] | EGFR/AKT | Chalcones |
| A549 cells IC50 = 3820 nmol/L MDA-MB-231 cells IC50 = 5890 nmol/L SKBR3 cells IC50 = 4790 nmol/L |
82 [181] | EGFR/HDACs | Pyrimidine-2-amines |
| EGFRWT IC50 = 5700 nmol/L EGFRT790M IC50 = 5000 nmol/L HDACs IC50 = 85 nmol/L A549 cells IC50 = 2190 nmol/L HeLa cells IC50 = 1850 nmol/L MDA-MB-231 cells IC50 = 600 nmol/L MDA-MB-468 cells IC50 = 230 nmol/L |
83 [182] | EGFR/PDGFR-β | Pyrimidine-2,4-diamines |
| EGFR Ki IC50 = 170 nmol/L PDGFR-β IC50 = 81 nmol/L |
84 [183] | EGFR/NF-κB | Quinazolines |
| EGFR IC50 = 60.1 nmol/L NF-κB IC50 = 300 nmol/L |
85 [184] | EGFR/c-Met | 1,2,4-Oxadiazole derivate |
| MDA-MB-231 cells IC50 = 200 nmol/L A459 cells IC50 = 200 nmol/L PC9 cells IC50 = 500 nmol/L H1975 cells IC50 = 300 nmol/L CL68 cells IC50 = 400 nmol/L CL97 cells IC50 = 500 nmol/L |
86 [185] | EGFRT790M/c-Met | Pyrimidine-2-amines |
| EGFRT790M IC50 = 97 nmol/L c-Met IC50 = 518 nmol/L |
87 [186] | EGFR/VEGFR-2 | Pyrimidine-2,4-diamines |
| EGFR Ki IC50 = 80 nmol/L VEGFR-2 Ki IC50 = 3240 nmol/L NCI-H460 cells GI = 25% (10 µmol/L) |
88 [187] | EGFR/VEGFR-2 | Quinazolines |
| EGFR IC50 = 1.0 nmol/L VEGFR-2 IC50 = 79.0 nmol/L HT-29 cells IC50 = 1760 nmol/L MCF7 cells IC50 = 7280 nmol/L |
89 [188] | EGFR/VEGFR-2 | Quinazolines |
| EGFR IC50 = 0.69 nmol/L VEGFR-2 IC50 = 67.84 nmol/L |
90 [59] | EGFR/VEGFR-2 | Quinazolines |
| EGFR IC50 = 2.0 nmol/L VEGFR-2 IC50 = 103.0 nmol/L A431 cells IC50 = 14.0 nmol/L H1975 cells IC50 = 130.0 nmol/L |
91 [189] | EGFR/VEGFR-2 | Quinazolines |
| EGFR IC50 = 20 nmol/L VEGFR-2 IC50 = 50 nmol/L |
92 [190] | EGFR/HER2 | Quinazolines |
| EGFR IC50 = 0.69 nmol/L HER2 IC50 = 42.1 nmol/L NCI-H1975 cells IC50 = 12.20 nmol/L HCC827 cells IC50 = 0.31 nmol/L A431 cells IC50 = 1.52 nmol/L MDA-MB-453 cells IC50 = 0.62 nmol/L |
93 [191] | EGFR/HER2 | Pyrimidine-4-amines |
| EGFR IC50 = 186 nmol/L VEGFR-2 IC50 = 254 nmol/L |
94 [192] | EGFR/HER2 | 3-Cyanoquizolines |
| EGFR IC50 = 597 nmol/L IGF1R IC50 = 908 nmol/L A431 cells IC50 = 1890 nmol/L SKBR3 cells IC50 = 1930 nmol/L |
EGFR/HER2 | Pyrimidinones |
| EGFR IC50 = 60 nmol/L HER2 IC50 = 300 nmol/L A549 cells IC50 = 280 nmol/L | |
96 [196] | EGFR/CSK | Chalcones |
| EGFR IC50 = 11,120 nmol/L CSK IC50 = 5160 nmol/L |
97 [197] | EGFR/CAIX | Quinazolines |
| EGFRWT IC50 = 27.0 nmol/L EGFRT790M IC50 = 9.2 nmol/L hCAII IC50 = 278.2 nmol/L hCAIX IC50 = 115.0 nmol/L A549 cells (hypoxia) IC50 = 2210 nmol/L A549 cells (normoxia) IC50 = 6450 nmol/L HeLa cells IC50 = 1850 nmol/L H1975 cells (hypoxia) IC50 = 1050 nmol/L H1975 cells (normoxia) IC50 = 1940 nmol/L |
