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RG, Capelletti M, Zhou W, Hur W, Kim N, Sim T, Gaudet S, Barbie DA, Yeh J-RJ, Yun C-H,
Hammerman PS, Mohammadi M, Jänne PA, Gray NS (2014) Development of covalent
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Funk JO (2017) Discovery of the irreversible covalent FGFR inhibitor
8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the treatment of solid
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117. Kalyukina M, Yosaatmadja Y, Middleditch MJ, Patterson AV, Smaill JB, Squire CJ (2019)
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Hodous B, Brooijmans N, Shutes A, Winter C, Lengauer C, Kohl NE, Guzi T (2015) First
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1158/2159-8290.CD-14-1029
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Bailey S, Wu J, Rimkunas V, Karr C, Subramanian V, Kumar P, MacKenzie C, Hurley R,
Satoh T, Yu K, Park E, Rioux N, Kim A, Lai WG, Yu L, Zhu P, Buonamici S, Larsen N,
Fekkes P, Wang J, Warmuth M, Reynolds DJ, Smith PG, Selvaraj A (2017) H3B-6527 is a
potent and selective inhibitor of FGFR4 in FGF19-driven hepatocellular carcinoma. Cancer
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121. Fairhurst AR, Knoepfel T, Leblanc C, Buschmann N, Gaul C, Blank J, Galuba I, Trappe J,
Zou C, Voshol J, Genick C, Brunet-Lefeuvre P, Bitsch F, Graus-Porta D, Furet P (2017)
Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the
ATP-pocket middle-hinge region. MedChemComm 8:1604–1613. https://doi.org/10.1039/
C7MD00213K
122. Yamaura T, Nakatani T, Uda K, Ogura H, Shin W, Kurokawa N, Saito K, Fujikawa N, Date T,
Takasaki M, Terada D, Hirai A, Akashi A, Chen F, Adachi Y, Ishikawa Y, Hayakawa F,
Hagiwara S, Naoe T, Kiyoi H (2018) A novel irreversible FLT3 inhibitor, FF-10101, shows
excellent efficacy against AML cells with FLT3 mutations. Blood 131:426–438. https://doi.
org/10.1182/blood-2017-05-786657
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1186/s12936-016-1580-3
111. Henise JC, Taunton J (2011) Irreversible Nek2 kinase inhibitors with cellular activity. J Med
Chem 54:4133–4146. https://doi.org/10.1021/jm200222m
112. Pearson RJ, Blake DG, Mezna M, Fischer PM, Westwood NJ, McInnes C (2018) The
Meisenheimer complex as a paradigm in drug discovery: reversible covalent inhibition
through C67 of the ATP binding site of PLK1. Cell Chem Biol 25:1107–1116.e4. https://
doi.org/10.1016/j.chembiol.2018.06.001
113. Dittus L, Werner T, Muelbaier M, Bantscheff M (2017) Differential kinobeads profiling for
target identification of irreversible kinase inhibitors. ACS Chem Biol 12:2515–2521. https://
doi.org/10.1021/acschembio.7b00617
114. Zhou W, Hur W, McDermott U, Dutt A, Xian W, Ficarro SB, Zhang J, Sharma SV, Brugge J,
Meyerson M, Settleman J, Gray NS (2010) A structure-guided approach to creating covalent
FGFR inhibitors. Chem Biol 17:285–295. https://doi.org/10.1016/j.chembiol.2010.02.007
115. Tan L, Wang J, Tanizaki J, Huang Z, Aref AR, Rusan M, Zhu S-J, Zhang Y, Ercan D, Liao
RG, Capelletti M, Zhou W, Hur W, Kim N, Sim T, Gaudet S, Barbie DA, Yeh J-RJ, Yun C-H,
Hammerman PS, Mohammadi M, Jänne PA, Gray NS (2014) Development of covalent
inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors. PNAS
111:E4869–E4877. https://doi.org/10.1073/pnas.1403438111
116. Brameld KA, Owens TD, Verner E, Venetsanakos E, Bradshaw JM, Phan VT, Tam D,
Leung K, Shu J, LaStant J, Loughhead DG, Ton T, Karr DE, Gerritsen ME, Goldstein DM,
Funk JO (2017) Discovery of the irreversible covalent FGFR inhibitor
8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the treatment of solid
tumors. J Med Chem 60:6516–6527. https://doi.org/10.1021/acs.jmedchem.7b00360
117. Kalyukina M, Yosaatmadja Y, Middleditch MJ, Patterson AV, Smaill JB, Squire CJ (2019)
TAS-120 cancer target binding: defining reactivity and revealing the first fibroblast growth
factor receptor 1 (FGFR1) irreversible structure. ChemMedChem 14:494–500. https://doi.org/
10.1002/cmdc.201800719
118. Kwarcinski FE, Fox CC, Steffey ME, Soellner MB (2012) Irreversible inhibitors of c-Src
kinase that target a nonconserved cysteine. ACS Chem Biol 7:1910–1917. https://doi.org/10.
1021/cb300337u
119. Hagel M, Miduturu C, Sheets M, Rubin N, Weng W, Stransky N, Bifulco N, Kim JL,
Hodous B, Brooijmans N, Shutes A, Winter C, Lengauer C, Kohl NE, Guzi T (2015) First
selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas
with an activated FGFR4 signaling pathway. Cancer Discov 5:424–437. https://doi.org/10.
1158/2159-8290.CD-14-1029
120. Joshi JJ, Coffey H, Corcoran E, Tsai J, Huang C-L, Ichikawa K, Prajapati S, Hao M-H,
Bailey S, Wu J, Rimkunas V, Karr C, Subramanian V, Kumar P, MacKenzie C, Hurley R,
Satoh T, Yu K, Park E, Rioux N, Kim A, Lai WG, Yu L, Zhu P, Buonamici S, Larsen N,
Fekkes P, Wang J, Warmuth M, Reynolds DJ, Smith PG, Selvaraj A (2017) H3B-6527 is a
potent and selective inhibitor of FGFR4 in FGF19-driven hepatocellular carcinoma. Cancer
Res 77:6999–7013. https://doi.org/10.1158/0008-5472.CAN-17-1865
121. Fairhurst AR, Knoepfel T, Leblanc C, Buschmann N, Gaul C, Blank J, Galuba I, Trappe J,
Zou C, Voshol J, Genick C, Brunet-Lefeuvre P, Bitsch F, Graus-Porta D, Furet P (2017)
Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the
ATP-pocket middle-hinge region. MedChemComm 8:1604–1613. https://doi.org/10.1039/
C7MD00213K
122. Yamaura T, Nakatani T, Uda K, Ogura H, Shin W, Kurokawa N, Saito K, Fujikawa N, Date T,
Takasaki M, Terada D, Hirai A, Akashi A, Chen F, Adachi Y, Ishikawa Y, Hayakawa F,
Hagiwara S, Naoe T, Kiyoi H (2018) A novel irreversible FLT3 inhibitor, FF-10101, shows
excellent efficacy against AML cells with FLT3 mutations. Blood 131:426–438. https://doi.
org/10.1182/blood-2017-05-786657
92
M. Gehringer