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(2019) A Triazolotriazine-based dual GSK-3β/CK-1δ ligand as a potential Neuroprotective
agent presenting two different mechanisms of enzymatic inhibition. ChemMedChem
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130. Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, Dastur A, Amzallag A,
Ramaswamy S, Tesar B, Jenkins CE, Hannett NM, McMillin D, Sanda T, Sim T, Kim ND,
Look T, Mitsiades CS, Weng AP, Brown JR, Benes CH, Marto JA, Young RA, Gray NS
(2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature
511:616. https://doi.org/10.1038/nature13393
131. Zhang T, Kwiatkowski N, Olson CM, Dixon-Clarke SE, Abraham BJ, Greifenberg AK,
Ficarro SB, Elkins JM, Liang Y, Hannett NM, Manz T, Hao M, Bartkowiak B, Greenleaf
AL, Marto JA, Geyer M, Bullock AN, Young RA, Gray NS (2016) Covalent targeting of
remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol
12:876–884. https://doi.org/10.1038/nchembio.2166
132. Gao Y, Zhang T, Terai H, Ficarro SB, Kwiatkowski N, Hao M-F, Sharma B, Christensen CL,
Chipumuro E, Wong K, Marto JA, Hammerman PS, Gray NS, George RE (2018) Overcoming
resistance to the THZ series of covalent transcriptional CDK inhibitors. Cell Chem Biol
25:135–142.e5. https://doi.org/10.1016/j.chembiol.2017.11.007
133. Andersen JL, Gesser B, Funder ED, Nielsen CJF, Gotfred-Rasmussen H, Rasmussen MK,
Toth R, Gothelf KV, Arthur JSC, Iversen L, Nissen P (2018) Dimethyl fumarate is an allosteric
covalent inhibitor of the p90 ribosomal S6 kinases. Nat Commun 9:4344. https://doi.org/10.
1038/s41467-018-06787-w
134. Dong T, Li C, Wang X, Dian L, Zhang X, Li L, Chen S, Cao R, Li L, Huang N, He S, Lei X
(2015) Ainsliadimer A selectively inhibits IKKα/β by covalently binding a conserved cysteine.
Nat Commun 6:ncomms7522. https://doi.org/10.1038/ncomms7522
Covalent Kinase Inhibitors: An Overview
93
Flemington V, Graham MA, Greenwood R, Hopcroft P, Howard TD, James M, Jones CD,
Jones CR, Renshaw J, Roberts K, Snow L, Tonge M, Yeung K (2015) Structure-guided design
of highly selective and potent covalent inhibitors of ERK1/2. J Med Chem 58:4790–4801.
https://doi.org/10.1021/acs.jmedchem.5b00466
124. Aronchik I, Dai Y, Labenski M, Barnes C, Jones T, QIao L, Beebe L, Malek M, Elis W, Shi T,
Mavrommatis K, Bray GL, Filvaroff EH (2018) Efficacy of a covalent ERK1/2 inhibitor,
CC-90003, in KRAS mutant cancer models reveals novel mechanisms of response and
resistance. Mol Cancer Res Mol 17:642–654. https://doi.org/10.1158/1541-7786.MCR-170554
125. Mita MM, LoRusso P, McArthur GA, Kim ES, Bray GL, Hock NH, Laille EJ, Aronchik I,
Filvaroff E, Wu X, Bendell JC (2017) A phase Ia study of CC-90003, a selective extracellular
signal-regulated kinase (ERK) inhibitor, in patients with relapsed or refractory BRAF or
RAS-mutant tumors. JCO 35:2577–2577. https://doi.org/10.1200/JCO.2017.35.15_suppl.
2577
126. Sipthorp J, Lebraud H, Gilley R, Kidger AM, Okkenhaug H, Saba-El-Leil M, Meloche S,
Caunt CJ, Cook SJ, Heightman TD (2017) Visualization of endogenous ERK1/2 in cells with a
bioorthogonal covalent probe. Bioconjug Chem 28:1677–1683. https://doi.org/10.1021/acs.
bioconjchem.7b00152
127. Yang Z, Liu H, Pan B, He F, Pan Z (2018) Design and synthesis of (aza)indolyl maleimidebased covalent inhibitors of glycogen synthase kinase 3β. Org Biomol Chem. https://doi.org/
10.1039/C8OB00642C
128. Wissner A, Fraser HL, Ingalls CL, Dushin RG, Floyd MB, Cheung K, Nittoli T, Ravi MR,
Tan X, Loganzo F (2007) Dual irreversible kinase inhibitors: Quinazoline-based inhibitors
incorporating two independent reactive centers with each targeting different cysteine residues
in the kinase domains of EGFR and VEGFR-2. Bioorg Med Chem 15:3635–3648. https://doi.
org/10.1016/j.bmc.2007.03.055
129. Redenti S, Marcovich I, De Vita T, Pérez C, De Zorzi R, Demitri N, Perez DI, Bottegoni G,
Bisignano P, Bissaro M, Moro S, Martinez A, Storici P, Spalluto G, Cavalli A, Federico S
(2019) A Triazolotriazine-based dual GSK-3β/CK-1δ ligand as a potential Neuroprotective
agent presenting two different mechanisms of enzymatic inhibition. ChemMedChem
14:310–314. https://doi.org/10.1002/cmdc.201800778
130. Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, Dastur A, Amzallag A,
Ramaswamy S, Tesar B, Jenkins CE, Hannett NM, McMillin D, Sanda T, Sim T, Kim ND,
Look T, Mitsiades CS, Weng AP, Brown JR, Benes CH, Marto JA, Young RA, Gray NS
(2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature
511:616. https://doi.org/10.1038/nature13393
131. Zhang T, Kwiatkowski N, Olson CM, Dixon-Clarke SE, Abraham BJ, Greifenberg AK,
Ficarro SB, Elkins JM, Liang Y, Hannett NM, Manz T, Hao M, Bartkowiak B, Greenleaf
AL, Marto JA, Geyer M, Bullock AN, Young RA, Gray NS (2016) Covalent targeting of
remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol
12:876–884. https://doi.org/10.1038/nchembio.2166
132. Gao Y, Zhang T, Terai H, Ficarro SB, Kwiatkowski N, Hao M-F, Sharma B, Christensen CL,
Chipumuro E, Wong K, Marto JA, Hammerman PS, Gray NS, George RE (2018) Overcoming
resistance to the THZ series of covalent transcriptional CDK inhibitors. Cell Chem Biol
25:135–142.e5. https://doi.org/10.1016/j.chembiol.2017.11.007
133. Andersen JL, Gesser B, Funder ED, Nielsen CJF, Gotfred-Rasmussen H, Rasmussen MK,
Toth R, Gothelf KV, Arthur JSC, Iversen L, Nissen P (2018) Dimethyl fumarate is an allosteric
covalent inhibitor of the p90 ribosomal S6 kinases. Nat Commun 9:4344. https://doi.org/10.
1038/s41467-018-06787-w
134. Dong T, Li C, Wang X, Dian L, Zhang X, Li L, Chen S, Cao R, Li L, Huang N, He S, Lei X
(2015) Ainsliadimer A selectively inhibits IKKα/β by covalently binding a conserved cysteine.
Nat Commun 6:ncomms7522. https://doi.org/10.1038/ncomms7522
Covalent Kinase Inhibitors: An Overview
93