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 - Funding Information:
This work was supported by grants Welch I-1829 (to K.D.W), CPRIT RP140233 (to K.D.W.), P50-GM107618 , U54HL127365 , U54-CA225088 , and KU-KIST Graduate School of Converging Science and Technology Program. S.R. would like to acknowledge the Jonathan M. Goldstein and Kaia Miller Goldstein Systems Pharmacology Fellowship and 3U54HL127365-02S1 (LINCS-IDG Collaboration) for supporting this work. We would like to thank HZB for the allocation of synchrotron radiation beamtime. Structural biology presented in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source which is operated by the University of Chicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. We thank the staff at the structural biology laboratory at UT Southwestern Medical Center and at beamline 19-ID of Advanced Photon Source, at BESSY beamline 14.2 and SLS X06SA for assistance with X-ray data collection.
Funding Information:
This work was supported by grants Welch I-1829 (to K.D.W), CPRIT RP140233 (to K.D.W.), P50-GM107618, U54HL127365, U54-CA225088, and KU-KIST Graduate School of Converging Science and Technology Program. S.R. would like to acknowledge the Jonathan M. Goldstein and Kaia Miller Goldstein Systems Pharmacology Fellowship and 3U54HL127365-02S1 (LINCS-IDG Collaboration) for supporting this work. We would like to thank HZB for the allocation of synchrotron radiation beamtime. Structural biology presented in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source which is operated by the University of Chicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. We thank the staff at the structural biology laboratory at UT Southwestern Medical Center and at beamline 19-ID of Advanced Photon Source, at BESSY beamline 14.2 and SLS X06SA for assistance with X-ray data collection. S.R. P.K.S. and N.S.G. designed the study and wrote the manuscript with input from co-authors. Experimental work was carried out by S.R. D.G. R.A.E. C.N.B. A.C. M.S. S.B.F. and K.D.W. Compounds were synthesized by G.D. and T.L. T.S. and N.D.K. carried out docking studies. M.B. assisted with proteomics. D.G. performed SRC crystallography with assistance from S.G. K.D.W. J.A.M. and S.K. reviewed and edited the manuscript. P.K.S. (orcid.org/0000-0002-3364-1838) established the profiling platforms and co-supervised S.R. R.A.E. and M.J.B. N.S.G. is a founder, science advisory board member (SAB) and equity holder in Gatekeeper, Syros, Petra, C4, B2S, and Soltego. The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Her2llc, Deerfield, and Sanofi. Peter K. Sorger is a founder, SAB member, and equity holder in Merrimack Pharmaceutical and Glencoe Software; he is on the Board of Directors of Applied Biomath and the SAB of RareCyte. In the last 5 years the Sorger lab has received research funding from Novartis and Merck. Sorger declares that none of these relationships are directly or indirectly related to the content of this manuscript.
Funding Information:
N.S.G. is a founder, science advisory board member (SAB) and equity holder in Gatekeeper, Syros, Petra, C4, B2S, and Soltego. The Gray lab receives or has received research funding from Novartis , Takeda , Astellas , Taiho , Janssen , Kinogen , Voronoi , Her2llc , Deerfield , and Sanofi . Peter K. Sorger is a founder, SAB member, and equity holder in Merrimack Pharmaceutical and Glencoe Software; he is on the Board of Directors of Applied Biomath and the SAB of RareCyte. In the last 5 years the Sorger lab has received research funding from Novartis and Merck . Sorger declares that none of these relationships are directly or indirectly related to the content of this manuscript.
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
UR - http://www.scopus.com/inward/record.url?scp=85067237871&partnerID=8YFLogxK
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 -
