8PT9

JNK1 covalently bound to BD838 cyclohexenone based inhibitor

Summary for 8PT9

• Entry DOI: 10.2210/pdb8pt9/pdb
• Descriptor: Mitogen-activated protein kinase 8, methyl (1S,3S)-1-methyl-3-[[3-[[3-methyl-4-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]carbamoyl]phenyl]carbamoyl]-4-oxidanylidene-cyclohexane-1-carboxylate (3 entities in total)
• Functional Keywords: mapk kinase, mapk, inhibitor, covalent, jnk, signaling protein, michael acceptor warhead
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 127875.63

Authors

Sok, P.,Poti, A.,Remenyi, A. (deposition date: 2023-07-13, release date: 2024-07-24, Last modification date: 2024-10-16)

Primary citation

Balint, D.,Poti, A.L.,Alexa, A.,Sok, P.,Albert, K.,Torda, L.,Foldesi-Nagy, D.,Csokas, D.,Turczel, G.,Imre, T.,Szarka, E.,Fekete, F.,Bento, I.,Bojtar, M.,Palko, R.,Szabo, P.,Monostory, K.,Papai, I.,Soos, T.,Remenyi, A.
Reversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads.
Nat Commun, 15:8606-8606, 2024

PubMed 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.

PubMed: 39366946
DOI: 10.1038/s41467-024-52573-2

Experimental method

X-RAY DIFFRACTION (2.7 Å)