Reversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads

被引：3

作者：

Balint, Daniel ^{[1
,2
]}

Poti, Adam Levente ^{[3
,4
]}

Alexa, Anita ^{[3
]}

Sok, Peter ^{[3
]}

Albert, Krisztian ^{[3
]}

Torda, Lili ^{[1
]}

Foldesi-Nagy, Dora ^{[3
]}

Csokas, Daniel ^{[5
]}

Turczel, Gabor ^{[6
]}

Imre, Timea ^{[7
]}

Szarka, Eszter ^{[3
]}

Fekete, Ferenc ^{[8
]}

Bento, Isabel ^{[9
]}

Bojtar, Marton ^{[10
]}

Palko, Roberta ^{[1
]}

Szabo, Pal ^{[7
]}

Monostory, Katalin ^{[8
]}

Papai, Imre ^{[5
]}

Soos, Tibor ^{[1
]}

Remenyi, Attila ^{[3
]}

机构：

[1] Res Ctr Nat Sci, Inst Organ Chem, Organocatalysis Res Grp, H-1117 Budapest, Hungary

[2] Eotvos Lorand Univ, Hevesy Gyorgy PhD Sch Chem, H-1117 Budapest, Hungary

[3] Res Ctr Nat Sci, Inst Organ Chem, Biomol Interact Res Grp, H-1117 Budapest, Hungary

[4] Eotvos Lorand Univ, Doctoral Sch Biol, H-1117 Budapest, Hungary

[5] Res Ctr Nat Sci, Inst Organ Chem, Theoret Chem Res Grp, H-1117 Budapest, Hungary

[6] Res Ctr Nat Sci, NMR Res Lab, Ctr Struct Sci, H-1117 Budapest, Hungary

[7] Res Ctr Nat Sci, Ctr Struct Sci, MS Metabol Res Lab, H-1117 Budapest, Hungary

[8] Res Ctr Nat Sci, Inst Mol Life Sci, Metab Drug Interact Res Grp, H-1117 Budapest, Hungary

[9] European Mol Biol Lab, EMBL, Hamburg, Germany

[10] Res Ctr Nat Sci, Inst Organ Chem, Chem Biol Res Grp, H-1117 Budapest, Hungary

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

关键词：

PROTEIN-KINASES; SIGNAL-TRANSDUCTION; RESIDENCE TIME; JNK; MAP; PATHWAY; ACTIVATION; DESIGN; POTENT;

D O I：

10.1038/s41467-024-52573-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

There has been a surge of interest in covalent inhibitors for protein kinases in recent years. Despite success in oncology, the off-target reactivity of these molecules is still hampering the use of covalent warhead-based strategies. Herein, we disclose the development of precision-guided warheads to mitigate the off-target challenge. These reversible warheads have a complex and cyclic structure with optional chirality center and tailored steric and electronic properties. To validate our proof-of-concept, we modified acrylamide-based covalent inhibitors of c-Jun N-terminal kinases (JNKs). We show that the cyclic warheads have high resilience against off-target thiols. Additionally, the binding affinity, residence time, and even JNK isoform specificity can be fine-tuned by adjusting the substitution pattern or using divergent and orthogonal synthetic elaboration of the warhead. Taken together, the cyclic warheads presented in this study will be a useful tool for medicinal chemists for the deliberate design of safer and functionally fine-tuned covalent inhibitors.

引用

页数：19

共 58 条

[1]

Boike L., Henning N.J., Nomura D.K., Advances in covalent drug discovery, Nat. Rev. Drug Discov, 21, pp. 881-898, (2022)

[2]

Roskoski R., Orally effective FDA-approved protein kinase targeted covalent inhibitors (TCIs), Pharmacol. Res, 165, (2021)

[3]

Krishnan S., Et al., Design of reversible, cysteine-targeted michael acceptors guided by kinetic and computational analysis, J. Am. Chem. Soc, 136, pp. 12624-12630, (2014)

[4]

Gehringer M., Laufer S.A., Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology, J. Med. Chem, 62, pp. 5673-5724, (2019)

[5]

Resnick E., Et al., Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening, J. Am. Chem. Soc, 141, pp. 8951-8968, (2019)

[6]

Liu Q., Et al., Developing irreversible inhibitors of the protein kinase cysteinome, Chem. Biol, 20, pp. 146-159, (2013)

[7]

Miller R.M., Taunton J., Targeting protein kinases with selective and semipromiscuous covalent inhibitors, Methods Enzymol, 548, pp. 93-116, (2014)

[8]

Zhao Z., Liu Q., Bliven S., Xie L., Bourne P.E., Determining Cysteines Available for Covalent Inhibition Across the Human Kinome, J. Med. Chem, 60, pp. 2879-2889, (2017)

[9]

Chaikuad A., Koch P., Laufer S.A., Knapp S., The Cysteinome of Protein Kinases as a Target in Drug Development, Angew. Chem. - Int. Ed, 57, pp. 4372-4385, (2018)

[10]

Jackson P.A., Widen J.C., Harki D.A., Brummond K.M., Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions, J. Med. Chem, 60, pp. 839-885, (2017)

← 1 2 3 4 5 6 →