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

Dániel Bálint, Ádám Levente Póti, Anita Alexa, Péter Sok, Krisztián Albert, Lili Torda, Dóra Földesi-Nagy, Dániel Csókás, Gábor Turczel, Tímea Imre, Eszter Szarka, Ferenc Fekete, Isabel Bento, Márton Bojtár, Roberta Palkó, Pál Szabó, Katalin Monostory, Imre Pápai, Tibor Soós () and Attila Reményi ()
Additional contact information
Dániel Bálint: Research Centre for Natural Sciences
Ádám Levente Póti: Research Centre for Natural Sciences
Anita Alexa: Research Centre for Natural Sciences
Péter Sok: Research Centre for Natural Sciences
Krisztián Albert: Research Centre for Natural Sciences
Lili Torda: Research Centre for Natural Sciences
Dóra Földesi-Nagy: Research Centre for Natural Sciences
Dániel Csókás: Research Centre for Natural Sciences
Gábor Turczel: Research Centre for Natural Sciences
Tímea Imre: Research Centre for Natural Sciences
Eszter Szarka: Research Centre for Natural Sciences
Ferenc Fekete: Research Centre for Natural Sciences
Isabel Bento: EMBL
Márton Bojtár: Research Centre for Natural Sciences
Roberta Palkó: Research Centre for Natural Sciences
Pál Szabó: Research Centre for Natural Sciences
Katalin Monostory: Research Centre for Natural Sciences
Imre Pápai: Research Centre for Natural Sciences
Tibor Soós: Research Centre for Natural Sciences
Attila Reményi: Research Centre for Natural Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52573-2

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