binding mode, showing favored inhibition of active phosphorylated class III 5-Ig
RTKs, comprising wild-type and mutant forms of the target proteins PDGFR-α,
PDGFR-β, and FLT3.
FLT3
614 KVLGS 618
690 IFEYCCYGD 698
818 LVTHGKVVKICDFG 831
PDGFR-α
597 RVLGS 601
673 ITEYCFYGD 681
825 LLAQGKIVKICDFG 838
PDGFR-β
604 RTLGS 608
680 ITEYCRYGD 688
833 LICEGKLVKICDFG 846
KIT
593 KTLGA 597
669 ITEYCCYGD 677
799 LLTHGRITKICDFG 812
VEGFR-I
831 KSLGR 835
908 IVEYCKYGN 916
1029 LLSENNVVKICDFG 1042
VEGFRII
838 KPLGR 842
915 IVEFCKFGN 923
1035 LLSEKNVVKICDFG 1048
EGFR
716 KVLGS 720
789 ITQLMPFGC 797
844 LVKTPQHVKITDFG 857
FGFR-1
482 KPLGE 486
560 IVEYASKGN 568
630 LVTEDNVMKIADFG 643
ABL
246 HKLGG 250
314 ITEFMTYGN 322
370 LVGENHLVKVADFG 383
gatekeeper
hinge
FLT3
L616
F691
Y693
C694
D698
L818
PDGFR-a
L599
T674
Y676
C677
D681
L825
PDGFR-b
L606
T681
Y683
C684
D688
L833
KIT
L595
T670
Y672
C673
D677
L799
VEGFR-I
L833
V909
Y911
C912
N916
L1029
VEGFR-II
L840
V916
F918
C919
N923
L1035
EGFR
L718
T790
L792
M793
C797
L844
FGFR-1
L484
V561
Y563
A564
N568
L630
ABL
L248
T315
F317
M318
N322
L370
Fig. 22 Sequence alignment and the modification of amino acid residues described as important for
crenolanib (63) recognition by FLT-3 in comparison with other relevant tyrosine kinases (TKs). For
all the class III 5-Ig RTKs, highlighted in green, the Asp amino acid residue involved in the ionic
electrostatic interaction with the charged amino group of drug candidate 63 is conserved. The amino
acid residues from FLT-3 are highlighted in brown, as well as those conserved in other PKs
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
191