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, Tı́mea Imre, Eszter Szarka, Ferenc Fekete, Isabel Bento, Márton Bojtár, Roberta Palkó, Pál Szabó, Katalin Monostory, Imre Pápai, Tibor Soós, Attila Reményi
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. Bálint et al utilized cyclohexenone and cyclopentenone based reversible covalent warheads to produce specific composite c-Jun N-terminal kinase inhibitors to demonstrate the modular nature of Michael acceptor based cyclic warhead designs.