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"Cysteinome" Assay Portfolio - potential targets for the rational development of irreversible inhibitors

In a recent publication (Liu Q.,et.al. 2013) they identify almost 200 kinases that contain a reactive nucleophilic cysteine residue near the ATP binding pocket, while suggesting that these kinases make promising targets of rationally designed irreversible kinase inhibitors.

Summary
  • Irreversible kinase inhibitors have tremendous therapeutic potential, including prolonged pharmacodynamics, high potency, pinpoint selectivity, and the potential to overcome disease resistance.
  • Kinases that contain a reactive nucleophilic cysteine residue near the ATP binding pocket are the ideal targets for novel irreversible inhibitors that are modified with an electrophilic moiety to selectively and covalently bind the cysteine of interest.
  • Research shows that nearly 200 kinases contain druggable cysteine residues for which irreversible inhibitors can be rationally designed from lead compounds
  • DiscoveRx offers 183 cysteine containing kinase assays, including mutants and other high value targets



Assay List

Gene Symbol Position Subposition Mutant
AAK1 DFG region, Hinge binding region DFG-1, Hinge2 No
AKT1 DFG region DFG+2 No
AKT2 DFG region DFG+2 No
AKT3 DFG region DFG+2 No
BIKE DFG region, Hinge binding region DFG-1, Hinge2 No
BLK Hinge binding region Hinge6 No
BMX Hinge binding region Hinge6 No
BRAF Hinge binding region Hinge2 No
BRAF(V600E) Hinge binding region Hinge2 Yes
BTK Hinge binding region Hinge6 No
CDK5 Hinge binding region Hinge2 No
CDK9 Hinge binding region Hinge2 No
CDKL1 DFG region, Hinge binding region DFG-1, Hinge2 No
CDKL2 DFG region DFG-1 No
CDKL3 DFG region DFG-1 No
CDKL5 DFG region DFG-1 No
CHEK1 Hinge binding region Hinge2 No
CSF1R Hinge binding region Hinge2, Hinge3 No
CSF1R-autoinhibited Hinge binding region Hinge2 No
DMPK DFG region DFG+2 No
DMPK2 DFG region DFG+2 No
EGFR Hinge binding region Hinge6 No
EGFR(E746-A750del) Hinge binding region Hinge6 Yes
EGFR(G719C) Hinge binding region Hinge6 Yes
EGFR(G719S) Hinge binding region Hinge6 Yes
EGFR(L747-E749del, A750P) Hinge binding region Hinge6 Yes
EGFR(L747-S752del, P753S) Hinge binding region Hinge6 Yes
EGFR(L747-T751del,Sins) Hinge binding region Hinge6 Yes
EGFR(L858R) Hinge binding region Hinge6 Yes
EGFR(L858R,T790M) Hinge binding region Hinge6 Yes
EGFR(L861Q) Hinge binding region Hinge6 Yes
EGFR(S752-I759del) Hinge binding region Hinge6 Yes
EGFR(T790M) Hinge binding region Hinge6 Yes
EPHB3 Hinge binding region Hinge5 No
ERBB2 Hinge binding region Hinge6 No
ERBB3 Glycine rich loop region, Roof region Glycineloop, Roof sheet No
ERBB4 Hinge binding region Hinge6 No
ERK1 DFG region DFG-1 No
ERK2 DFG region DFG-1 No
ERN1 DFG region, Hinge binding region DFG+2, Hinge2 No
FAK Hinge binding region Hinge2 No
FGFR1 Glycine rich loop region Glycineloop5 No
FGFR2 Glycine rich loop region Glycineloop5 No
FGFR3 Glycine rich loop region Glycineloop5 No
FGFR3(G697C) Glycine rich loop region Glycineloop5 Yes
FGFR4 Glycine rich loop region, Hing binding region Glycineloop5, Hinge1 No
FGR Hinge binding region Hinge3 No
FLT1 DFG region, Hinge binding region DFG-1, Hinge2 No
FLT3 DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 No
FLT3(D835H) DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 Yes
FLT3(D835Y) DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 Yes
FLT3(ITD) DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 Yes
FLT3(K663Q) DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 Yes
FLT3(N841I) DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 Yes
FLT3(R834Q) DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 Yes
FLT3-autoinhibited DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 No
FLT4 DFG region, Hinge binding region DFG-1, Hinge2 No
GAK DFG region, Hinge binding region DFG-1, Hinge2 No
GCN2(Kin.Dom.2,S808G) Hinge binding region Hinge2 Yes
GSK3A DFG region DFG-1 No
GSK3B DFG region DFG-1 No
HPK1 Gatekeeper, Hinge binding region GK-1, Hinge2 No
HUNK Hinge binding region Hinge2 No
IKK-alpha Hinge binding region Hinge2 No
IKK-beta Hinge binding region Hinge2 No
IKK-epsilon Hinge binding region Hinge2 No
ITK Hinge binding region Hinge6 No
JAK3(JH1domain-catalytic) Hinge binding region Hinge6 No
JNK1 Hinge binding region Hinge7 No
JNK2 Hinge binding region Hinge7 No
JNK3 Hinge binding region Hinge7 No
KIT DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 No
KIT(A829P) DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 Yes
KIT(D816H) DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 Yes
KIT(D816V) DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 Yes
KIT(L576P) DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 Yes
KIT(V559D) DFG region, Hinge binding region DFG-1, Hinge2, Hinge3 Yes
KIT(V559D,T670I) DFG region, Hinge binding region DFG-1, Hinge2 Yes
KIT(V559D,V654A) DFG region, Hinge binding region DFG-1, Hinge2 Yes
KIT-autoinhibited DFG region, Hinge binding region DFG-1, Hinge2 No
LKB1 Hinge binding region Hinge2, Hinge4 No
LOK Hinge binding region Hinge2 No
LZK Hinge binding region Hinge2 No
MAP3K4 DFG region, Hinge binding region DFG+1, Hinge2 No
MAP4K3 Gatekeeper, Hinge binding region GK-1, Hinge2 No
MAP4K4 Hinge binding region Hinge2 No
MAP4K5 Gatekeeper, Hinge binding region GK-1, Hinge2 No
MAPKAPK2 Hinge binding region Hinge1 No
MAPKAPK5 DFG region DFG-1 No
MEK1 Gatekeeper, DFG region GK-1, DGF-1 No
MEK2 Gatekeeper, DFG region GK-1, DGF-1 No
MEK3 Gatekeeper, DFG region GK-1, DGF-1 No
MEK4 Gatekeeper, DFG region GK-1, DGF-1 No
MEK5 Gatekeeper, DFG region GK-1, DGF-1 No
MEK6 Gatekeeper, DFG region GK-1, DGF-1 No
MELK DFG region, Hinge binding region DFG+2, Hinge2 No
MINK Hinge binding region Hinge2 No
MKK7 DFG region, Hinge binding region DFG-1, Hinge6 No
MKNK1 DFG region DFG-1 No
MKNK2 DFG region DFG-1 No
MRCKB DFG region DFG+2 No
MST1 Hinge binding region Hinge2 No
MST1R Hinge binding region Hinge3 No
MST2 Hinge binding region Hinge2 No
MYO3A Hinge binding region Hinge2 No
MYO3B Hinge binding region Hinge2 No
NDR1 DFG region DFG+2 No
NDR2 DFG region DFG+2 No
NEK1 Hinge binding region Hinge2 No
NEK11 Hinge binding region Hinge2 No
NEK2 Glycine rich loop region, Hing binding region Glycineloop2, Hinge2 No
NEK3 Hinge binding region Hinge2 No
NEK4 Hinge binding region Hinge2 No
NEK5 Hinge binding region Hinge2 No
NEK9 Hinge binding region Hinge2 No
NIK DFG region DFG-1 No
NLK DFG region DFG-1 No
PAK1 DFG region DFG+2 No
PAK2 DFG region DFG+2 No
PAK3 DFG region DFG+2 No
PAK4 DFG region DFG+2 No
PAK6 DFG region DFG+2 No
PDGFRA DFG region, Hinge binding region DFG-1, Hinge2 No
PDGFRB DFG region, Hinge binding region DFG-1, Hinge2 No
PKN1 DFG region DFG+2 No
PKN2 DFG region DFG+2 No
PLK1 Glycine rich loop region, Hing binding region Glycineloop2, Hinge2 No
PLK2 Glycine rich loop region, Hing binding region Glycineloop2, Hinge2 No
PLK3 Glycine rich loop region, Hing binding region Glycineloop2, Hinge2 No
PLK4 Hinge binding region Hinge2 No
PRKCD DFG region DFG+2 No
PRKCE DFG region DFG+2 No
PRKCI DFG region DFG+2 No
PRKCQ DFG region DFG+2 No
PRKD1 DFG region DFG-1 No
PRKD2 DFG region DFG-1 No
PRKD3 DFG region DFG-1 No
PRKG1 Hinge binding region Hinge2 No
PRKG2 Hinge binding region Hinge2 No
PRKR Hinge binding region Hinge2 No
PRP4 DFG region DFG-1 No
RAF1 Hinge binding region Hinge2 Yes
RIPK5 DFG region, Glycine rich loop region DFG+2, Glycineloop2 No
ROCK1 DFG region DFG+2 No
ROCK2 DFG region DFG+2 No
RPS6KA4(Kin.Dom.2-C-terminal) Glycine rich loop region Glycineloop2 No
RPS6KA5(Kin.Dom.2-C-terminal) Glycine rich loop region Glycineloop2 No
RSK1(Kin.Dom.1-N-terminal) DFG region DFG-1 No
RSK1(Kin.Dom.2-C-terminal) DFG region, Glycine rich loop region DFG-1, Glycineloop2 No
RSK2(Kin.Dom.1-N-terminal) DFG region DFG-1 No
RSK2(Kin.Dom.2-C-terminal) DFG region, Glycine rich loop region DFG-1, Glycineloop2 No
RSK3(Kin.Dom.1-N-terminal) DFG region DFG-1 No
RSK3(Kin.Dom.2-C-terminal) DFG region, Glycine rich loop region DFG-1, Glycineloop2 No
RSK4(Kin.Dom.1-N-terminal) DFG region DFG-1 No
RSK4(Kin.Dom.2-C-terminal) DFG region, Glycine rich loop region DFG-1, Glycineloop2 No
S6K1 DFG region DFG+2 No
SgK110 Hinge binding region Hinge4 No
SGK2 DFG region DFG+2 No
SGK3 DFG region DFG+2 No
SLK Hinge binding region Hinge2 No
STK33 Hinge binding region Hinge2 No
STK35 Hinge binding region Hinge2 No
TAK1 DFG region DFG-1 No
TAOK1 Hinge binding region Hinge2 No
TAOK2 Hinge binding region Hinge2 No
TAOK3 Hinge binding region Hinge2 No
TBK1 Hinge binding region Hinge2, Hinge4 No
TEC Hinge binding region Hinge6 No
TGFBR2 DFG region DFG-1 No
TLK1 Hinge binding region Hinge2 No
TLK2 Hinge binding region Hinge2 No
TNIK Hinge binding region Hinge2 No
TTK Hinge binding region Hinge1 No
TXK Hinge binding region Hinge6 No
ULK1 Hinge binding region Hinge2 No
ULK2 Hinge binding region Hinge2 No
ULK3 Hinge binding region Hinge2 No
VEGFR2 DFG region, Hinge binding region DFG-1, Hinge2 No
WEE1 Hinge binding region Hinge2 No
WEE2 Hinge binding region Hinge2 No
WNK1 Glycine rich loop region Glycineloop No
WNK3 Glycine rich loop region Glycineloop No
ZAK DFG region, Glycine rich loop region DFG-1, Glycineloop1 No