1. Reversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads.
- Author
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Bálint D, Póti ÁL, Alexa A, Sok P, Albert K, Torda L, Földesi-Nagy D, Csókás D, Turczel G, Imre T, Szarka E, Fekete F, Bento I, Bojtár M, Palkó R, Szabó P, Monostory K, Pápai I, Soós T, and Reményi A
- Subjects
- Humans, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Cysteine chemistry, Cysteine metabolism, JNK Mitogen-Activated Protein Kinases antagonists & inhibitors, JNK Mitogen-Activated Protein Kinases metabolism
- 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., (© 2024. The Author(s).)
- Published
- 2024
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