Marotti M, Rukazenkov Y, Ramalingam SS (2017) Osimertinib in untreated EGFR-mutated
advanced non–small-cell lung cancer. N Engl J Med 378:113–125. https://doi.org/10.1056/
NEJMoa1713137
45. Barf T, Covey T, Izumi R, van de Kar B, Gulrajani M, van Lith B, van Hoek M, de Zwart E,
Mittag D, Demont D, Verkaik S, Krantz F, Pearson PG, Ulrich R, Kaptein A (2017)
Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated
selectivity and in vivo potency profile. J Pharmacol Exp Ther 363:240–252. https://doi.org/10.
1124/jpet.117.242909
46. Shirley M (2018) Dacomitinib: first global approval. Drugs. https://doi.org/10.1007/s40265018-1028-x
47. Lagoutte R, Winssinger N (2017) Following the lead from nature with covalent inhibitors.
CHIMIA Int J Chem 71:703–711. https://doi.org/10.2533/chimia.2017.703
48. Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, Pirola L, Vanhaesebroeck B, Waterfield MD,
Panayotou G (1996) Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol Cell Biol
16:1722–1733. https://doi.org/10.1128/MCB.16.4.1722
49. Zhao A, Lee SH, Moiena M, Jenkins RG, Patrick DR, Huber HE, Goetz MA, Hensens OD,
Zink DL, Vilella D, Dombrowski AW, Lingham RB, Huang L (1999) Resorcylic acid
lactones: naturally occurring potent and selective inhibitors of MEK. J Antibiot
52:1086–1094. https://doi.org/10.7164/antibiotics.52.1086
50. Williams DH, Wilkinson SE, Purton T, Lamont A, Flotow H, Murray EJ (1998) Ro 09-2210
exhibits potent anti-proliferative effects on activated T cells by selectively blocking MKK
activity. Biochemistry 37:9579–9585. https://doi.org/10.1021/bi972914c
51. Rastelli G, Rosenfeld R, Reid R, Santi DV (2008) Molecular modeling and crystal structure of
ERK2–hypothemycin complexes. J Struct Biol 164:18–23. https://doi.org/10.1016/j.jsb.2008.
05.002
52. Schirmer A, Kennedy J, Murli S, Reid R, Santi DV (2006) Targeted covalent inactivation of
protein kinases by resorcylic acid lactone polyketides. PNAS 103:4234–4239. https://doi.org/
10.1073/pnas.0600445103
53. Wu J, Powell F, Larsen NA, Lai Z, Byth KF, Read J, Gu R-F, Roth M, Toader D, Saeh JC,
Chen H (2013) Mechanism and in vitro pharmacology of TAK1 inhibition by (5Z)-7Oxozeaenol. ACS Chem Biol 8:643–650. https://doi.org/10.1021/cb3005897
54. Sogabe Y, Matsumoto T, Hashimoto T, Kirii Y, Sawa M, Kinoshita T (2015) 5Z-7Oxozeaenol covalently binds to MAP2K7 at Cys218 in an unprecedented manner. Bioorg
Med Chem Lett 25:593–596. https://doi.org/10.1016/j.bmcl.2014.12.011
55. Shen Y, Boivin R, Yoneda N, Du H, Schiller S, Matsushima T, Goto M, Shirota H,
Gusovsky F, Lemelin C, Jiang Y, Zhang Z, Pelletier R, Ikemori-Kawada M, Kawakami Y,
Inoue A, Schnaderbeck M, Wang Y (2010) Discovery of anti-inflammatory clinical candidate
E6201, inspired from resorcylic lactone LL-Z1640-2, III. Bioorg Med Chem Lett
20:3155–3157. https://doi.org/10.1016/j.bmcl.2010.03.087
56. Borthakur G, Gao C, Chen Y, Lan YS, Ruvolo VR, Nomoto K, Zhao N, Konopleva M,
Andreeff M (2013) Study of activity of E6201, a dual FLT3 and MEK inhibitor, in acute
Myelogenous leukemia with FLT3 or RAS mutation. Blood 122:2683–2683
57. Rossi A, Kapahi P, Natoli G, Takahashi T, Chen Y, Karin M, Santoro MG (2000) Antiinflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature
403:103–118. https://doi.org/10.1038/47520
58. Toral-Barza L, Zhang W-G, Huang X, McDonald LA, Salaski EJ, Barbieri LR, Ding W-D,
Krishnamurthy G, Hu YB, Lucas J, Bernan VS, Cai P, Levin JI, Mansour TS, Gibbons JJ,
Abraham RT, Yu K (2007) Discovery of lactoquinomycin and related pyranonaphthoquinones
as potent and allosteric inhibitors of AKT/PKB: mechanistic involvement of AKT catalytic
activation loop cysteines. Mol Cancer Ther 6:3028–3038. https://doi.org/10.1158/1535-7163.
MCT-07-0211
Covalent Kinase Inhibitors: An Overview
87
advanced non–small-cell lung cancer. N Engl J Med 378:113–125. https://doi.org/10.1056/
NEJMoa1713137
45. Barf T, Covey T, Izumi R, van de Kar B, Gulrajani M, van Lith B, van Hoek M, de Zwart E,
Mittag D, Demont D, Verkaik S, Krantz F, Pearson PG, Ulrich R, Kaptein A (2017)
Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated
selectivity and in vivo potency profile. J Pharmacol Exp Ther 363:240–252. https://doi.org/10.
1124/jpet.117.242909
46. Shirley M (2018) Dacomitinib: first global approval. Drugs. https://doi.org/10.1007/s40265018-1028-x
47. Lagoutte R, Winssinger N (2017) Following the lead from nature with covalent inhibitors.
CHIMIA Int J Chem 71:703–711. https://doi.org/10.2533/chimia.2017.703
48. Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, Pirola L, Vanhaesebroeck B, Waterfield MD,
Panayotou G (1996) Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol Cell Biol
16:1722–1733. https://doi.org/10.1128/MCB.16.4.1722
49. Zhao A, Lee SH, Moiena M, Jenkins RG, Patrick DR, Huber HE, Goetz MA, Hensens OD,
Zink DL, Vilella D, Dombrowski AW, Lingham RB, Huang L (1999) Resorcylic acid
lactones: naturally occurring potent and selective inhibitors of MEK. J Antibiot
52:1086–1094. https://doi.org/10.7164/antibiotics.52.1086
50. Williams DH, Wilkinson SE, Purton T, Lamont A, Flotow H, Murray EJ (1998) Ro 09-2210
exhibits potent anti-proliferative effects on activated T cells by selectively blocking MKK
activity. Biochemistry 37:9579–9585. https://doi.org/10.1021/bi972914c
51. Rastelli G, Rosenfeld R, Reid R, Santi DV (2008) Molecular modeling and crystal structure of
ERK2–hypothemycin complexes. J Struct Biol 164:18–23. https://doi.org/10.1016/j.jsb.2008.
05.002
52. Schirmer A, Kennedy J, Murli S, Reid R, Santi DV (2006) Targeted covalent inactivation of
protein kinases by resorcylic acid lactone polyketides. PNAS 103:4234–4239. https://doi.org/
10.1073/pnas.0600445103
53. Wu J, Powell F, Larsen NA, Lai Z, Byth KF, Read J, Gu R-F, Roth M, Toader D, Saeh JC,
Chen H (2013) Mechanism and in vitro pharmacology of TAK1 inhibition by (5Z)-7Oxozeaenol. ACS Chem Biol 8:643–650. https://doi.org/10.1021/cb3005897
54. Sogabe Y, Matsumoto T, Hashimoto T, Kirii Y, Sawa M, Kinoshita T (2015) 5Z-7Oxozeaenol covalently binds to MAP2K7 at Cys218 in an unprecedented manner. Bioorg
Med Chem Lett 25:593–596. https://doi.org/10.1016/j.bmcl.2014.12.011
55. Shen Y, Boivin R, Yoneda N, Du H, Schiller S, Matsushima T, Goto M, Shirota H,
Gusovsky F, Lemelin C, Jiang Y, Zhang Z, Pelletier R, Ikemori-Kawada M, Kawakami Y,
Inoue A, Schnaderbeck M, Wang Y (2010) Discovery of anti-inflammatory clinical candidate
E6201, inspired from resorcylic lactone LL-Z1640-2, III. Bioorg Med Chem Lett
20:3155–3157. https://doi.org/10.1016/j.bmcl.2010.03.087
56. Borthakur G, Gao C, Chen Y, Lan YS, Ruvolo VR, Nomoto K, Zhao N, Konopleva M,
Andreeff M (2013) Study of activity of E6201, a dual FLT3 and MEK inhibitor, in acute
Myelogenous leukemia with FLT3 or RAS mutation. Blood 122:2683–2683
57. Rossi A, Kapahi P, Natoli G, Takahashi T, Chen Y, Karin M, Santoro MG (2000) Antiinflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature
403:103–118. https://doi.org/10.1038/47520
58. Toral-Barza L, Zhang W-G, Huang X, McDonald LA, Salaski EJ, Barbieri LR, Ding W-D,
Krishnamurthy G, Hu YB, Lucas J, Bernan VS, Cai P, Levin JI, Mansour TS, Gibbons JJ,
Abraham RT, Yu K (2007) Discovery of lactoquinomycin and related pyranonaphthoquinones
as potent and allosteric inhibitors of AKT/PKB: mechanistic involvement of AKT catalytic
activation loop cysteines. Mol Cancer Ther 6:3028–3038. https://doi.org/10.1158/1535-7163.
MCT-07-0211
Covalent Kinase Inhibitors: An Overview
87