9DCD

Structure of J-PKAc chimera in complex with Aplithianine d2

これはPDB形式変換不可エントリーです。

9DCD の概要

• エントリーDOI: 10.2210/pdb9dcd/pdb
• 分子名称: cAMP-dependent protein kinase catalytic subunit alpha, cAMP-dependent protein kinase inhibitor alpha, N-(2-aminoethyl)-4-(7H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxamide, ... (4 entities in total)
• 機能のキーワード: protein kinase a, fibrolamellar hepatocellular carcinoma, natural product, signaling protein, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 43289.12

構造登録者

Martinez Fiesco, J.A.,Zhang, P. (登録日: 2024-08-25, 公開日: 2025-07-09)

主引用文献

Du, L.,Wilson, B.A.P.,Moore, W.J.,Dalilian, M.,Shenoy, S.R.,Li, N.,Martinez Fiesco, J.A.,Hwang, J.Y.,Smith, E.A.,Wamiru, A.,Goncharova, E.I.,Alvarez de la Cruz, A.,Pagadala, K.,Piswa, H.K.,Patteti, V.,Jampana, V.P.,Manepalli, P.,Nimmala, R.,Marri, N.R.,Gunuguntla, M.,Reddy, J.J.,Schneekloth Jr., J.S.,Zhang, P.,O'Keefe, B.R.
Chemical Evolution of Aplithianine Class of Serine/Threonine Kinase Inhibitors.
J.Med.Chem., 68:12756-12785, 2025

PubMed Abstract: Chimeric kinase J-PKAcα represents a potential therapeutic target for fibrolamellar hepatocellular carcinoma (FLHCC). Structure-based design and screening were applied to improve the potency of the marine-derived kinase inhibitor aplithianine A targeting J-PKAcα. Three classes of aplithianines (I, II, and III) including >150 analogs were synthesized, significantly improving biochemical IC values to the low nanomolar range. X-ray diffraction experiments confirmed that the class II aplithianines adopted a novel binding mode to J-PKAcα by interacting with the DFG residue Asp239. The kinase selectivity profiles were assessed by kinome profiling. profiles of selected class II analogs were evaluated to determine compound solubility, protein binding, permeability, metabolism, and hERG binding. Selected aplithianine analogs inhibited intracellular phosphorylation of the peptide substrate CREB following stimulation of the J-PKAcα fusion kinase in NIH/3T3 cells and exhibited antiproliferative/cytotoxic activities against select cancer cell lines from the NCI-60 cell panel at nanomolar concentrations.

PubMed: 40476486
DOI: 10.1021/acs.jmedchem.5c00649

実験手法

X-RAY DIFFRACTION (2.7 Å)