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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
95 [193,194,195] 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