8PTA
JNK1 covalently bound to BD837 cyclohexenone based inhibitor
Summary for 8PTA
| Entry DOI | 10.2210/pdb8pta/pdb |
| Descriptor | Mitogen-activated protein kinase 8, methyl (1R,3S)-1-methyl-3-[[3-[[3-methyl-4-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]carbamoyl]phenyl]carbamoyl]-4-oxidanylidene-cyclohexane-1-carboxylate, GLYCEROL, ... (4 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 | 127967.72 |
| 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 Cited by 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: 39366946DOI: 10.1038/s41467-024-52573-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.41 Å) |
Structure validation
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