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Structure-based design, synthesis and crystallization of 2-arylquinazolines as lipid pocket ligands of p38α MAPK.

Bührmann M, Wiedemann BM, Müller MP, Hardick J, Ecke M, Rauh D
PLoS One 12 e0184627 (2017)
Related entries: 5n63, 5n64, 5n66, 5n67, 5n68

Cited: 7 times
EuropePMC logo PMID: 28892510

Abstract

In protein kinase research, identifying and addressing small molecule binding sites other than the highly conserved ATP-pocket are of intense interest because this line of investigation extends our understanding of kinase function beyond the catalytic phosphotransfer. Such alternative binding sites may be involved in altering the activation state through subtle conformational changes, control cellular enzyme localization, or in mediating and disrupting protein-protein interactions. Small organic molecules that target these less conserved regions might serve as tools for chemical biology research and to probe alternative strategies in targeting protein kinases in disease settings. Here, we present the structure-based design and synthesis of a focused library of 2-arylquinazoline derivatives to target the lipophilic C-terminal binding pocket in p38α MAPK, for which a clear biological function has yet to be identified. The interactions of the ligands with p38α MAPK was analyzed by SPR measurements and validated by protein X-ray crystallography.

Articles - 5n65 mentioned but not cited (3)

  1. Structure-based design, synthesis and crystallization of 2-arylquinazolines as lipid pocket ligands of p38α MAPK. Bührmann M, Wiedemann BM, Müller MP, Hardick J, Ecke M, Rauh D. PLoS One 12 e0184627 (2017)
  2. Targeting the non-ATP-binding pocket of the MAP kinase p38γ mediates a novel mechanism of cytotoxicity in cutaneous T-cell lymphoma (CTCL). Zhang XH, Chen CH, Li H, Hsiang J, Wu X, Hu W, Horne D, Nam S, Shively J, Rosen ST. FEBS Lett 595 2570-2592 (2021)
  3. Druggable exosites of the human kino-pocketome. Nicola G, Kufareva I, Ilatovskiy AV, Abagyan R. J Comput Aided Mol Des 34 219-230 (2020)


Articles citing this publication (4)

  1. Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation. Juyoux P, Galdadas I, Gobbo D, von Velsen J, Pelosse M, Tully M, Vadas O, Gervasio FL, Pellegrini E, Bowler MW. Science 381 1217-1225 (2023)
  2. Characterization of p38α autophosphorylation inhibitors that target the non-canonical activation pathway. González L, Díaz L, Pous J, Baginski B, Duran-Corbera A, Scarpa M, Brun-Heath I, Igea A, Martin-Malpartida P, Ruiz L, Pallara C, Esguerra M, Colizzi F, Mayor-Ruiz C, Biondi RM, Soliva R, Macias MJ, Orozco M, Nebreda AR. Nat Commun 14 3318 (2023)
  3. Novel method to identify group-specific non-catalytic pockets of human kinome for drug design. Wang H, Guan Z, Qiu J, Jia Y, Zeng C, Zhao Y. RSC Adv 10 2004-2015 (2020)
  4. Design, synthesis, and study of novel phenethyl-based antitumor phospholipids downregulating p38 mitogen-activated protein kinase. Hassan AHE, Oh YI, Lee CH, Kim YJ, Cho SB, Alam MM, Park SE, Chung KS, Lee KT, Lee YS. J Enzyme Inhib Med Chem 38 2217695 (2023)


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