TY - JOUR
T1 - Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome
AU - Rao, Suman
AU - Gurbani, Deepak
AU - Du, Guangyan
AU - Everley, Robert A.
AU - Browne, Christopher M.
AU - Chaikuad, Apirat
AU - Tan, Li
AU - Schröder, Martin
AU - Gondi, Sudershan
AU - Ficarro, Scott B.
AU - Sim, Taebo
AU - Kim, Nam Doo
AU - Berberich, Matthew J.
AU - Knapp, Stefan
AU - Marto, Jarrod A.
AU - Westover, Kenneth D.
AU - Sorger, Peter K.
AU - Gray, Nathanael S.
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/6/20
Y1 - 2019/6/20
N2 - Covalent kinase inhibitors, which typically target cysteine residues, represent an important class of clinically relevant compounds. Approximately 215 kinases are known to have potentially targetable cysteines distributed across 18 spatially distinct locations proximal to the ATP-binding pocket. However, only 40 kinases have been covalently targeted, with certain cysteine sites being the primary focus. To address this disparity, we have developed a strategy that combines the use of a multi-targeted acrylamide-modified inhibitor, SM1-71, with a suite of complementary chemoproteomic and cellular approaches to identify additional targetable cysteines. Using this single multi-targeted compound, we successfully identified 23 kinases that are amenable to covalent inhibition including MKNK2, MAP2K1/2/3/4/6/7, GAK, AAK1, BMP2K, MAP3K7, MAPKAPK5, GSK3A/B, MAPK1/3, SRC, YES1, FGFR1, ZAK (MLTK), MAP3K1, LIMK1, and RSK2. The identification of nine of these kinases previously not targeted by a covalent inhibitor increases the number of targetable kinases and highlights opportunities for covalent kinase inhibitor development. The current work by Rao et al. describes using a promiscuous ligand as a tool to identify new targets for drug discovery. The findings from this study highlight previously unknown targets against which irreversible inhibitors can be developed. These targets are typically deregulated in diseases including cancer.
AB - Covalent kinase inhibitors, which typically target cysteine residues, represent an important class of clinically relevant compounds. Approximately 215 kinases are known to have potentially targetable cysteines distributed across 18 spatially distinct locations proximal to the ATP-binding pocket. However, only 40 kinases have been covalently targeted, with certain cysteine sites being the primary focus. To address this disparity, we have developed a strategy that combines the use of a multi-targeted acrylamide-modified inhibitor, SM1-71, with a suite of complementary chemoproteomic and cellular approaches to identify additional targetable cysteines. Using this single multi-targeted compound, we successfully identified 23 kinases that are amenable to covalent inhibition including MKNK2, MAP2K1/2/3/4/6/7, GAK, AAK1, BMP2K, MAP3K7, MAPKAPK5, GSK3A/B, MAPK1/3, SRC, YES1, FGFR1, ZAK (MLTK), MAP3K1, LIMK1, and RSK2. The identification of nine of these kinases previously not targeted by a covalent inhibitor increases the number of targetable kinases and highlights opportunities for covalent kinase inhibitor development. The current work by Rao et al. describes using a promiscuous ligand as a tool to identify new targets for drug discovery. The findings from this study highlight previously unknown targets against which irreversible inhibitors can be developed. These targets are typically deregulated in diseases including cancer.
KW - chemical probe
KW - chemoproteomics
KW - covalent inhibitors
KW - crystal structure
KW - cysteines
KW - drug discovery
KW - kinase inhibitors
KW - kinobeads
KW - multi-targeted compounds
KW - target engagement
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U2 - 10.1016/j.chembiol.2019.02.021
DO - 10.1016/j.chembiol.2019.02.021
M3 - Article
C2 - 30982749
AN - SCOPUS:85067237871
SN - 2451-9456
VL - 26
SP - 818-829.e9
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 6
ER -