8bzp
From Proteopedia
JNK3 (Mitogen-activated protein kinase 10) in Complex with Compound 23 bearing a C(sp3)F2Br moiety
Structural highlights
DiseaseMK10_HUMAN Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:606369. Epileptic encephalopathies of the Lennox-Gastaut group are childhood epileptic disorders characterized by severe psychomotor delay and seizures. Note=A chromosomal aberration involving MAPK10 has been found in a single patient. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation. FunctionMK10_HUMAN Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the beta-amyloid precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons.[1] Publication Abstract from PubMedAs an orthogonal principle to the established (hetero)aryl halides, we herein highlight the usefulness of CF(2)X (X = Cl, Br, or I) moieties. Using tool compounds bearing CF(2)X moieties, we study their chemical/metabolic stability and their logP/solubility, as well as the role of XB in their small molecular crystal structures. Employing QM techniques, we analyze the observed interactions, provide insights into the conformational flexibilities and preferences in the potential interaction space. For their application in molecular design, we characterize their XB donor capacities and its interaction strength dependent on geometric parameters. Implementation of CF(2)X acetamides into our HEFLibs and biophysical evaluation (STD-NMR/ITC), followed by X-ray analysis, reveals a highly interesting binding mode for fragment 23 in JNK3, featuring an XB of CF(2)Br toward the P-loop, as well as chalcogen bonds. We suggest that underexplored chemical space combined with unconventional binding modes provides excellent opportunities for patentable chemotypes for therapeutic intervention. Principles and Applications of CF(2)X Moieties as Unconventional Halogen Bond Donors in Medicinal Chemistry, Chemical Biology, and Drug Discovery.,Vaas S, Zimmermann MO, Schollmeyer D, Stahlecker J, Engelhardt MU, Rheinganz J, Drotleff B, Olfert M, Lammerhofer M, Kramer M, Stehle T, Boeckler FM J Med Chem. 2023 Jul 24. doi: 10.1021/acs.jmedchem.3c00634. PMID:37487500[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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