4JG6

RSK2 CTD bound to 2-cyano-3-(1H-indazol-5-yl)acrylamide

Summary for 4JG6

• Entry DOI: 10.2210/pdb4jg6/pdb
• Descriptor: Ribosomal protein S6 kinase alpha-3, (2S)-2-cyano-3-(1H-indazol-5-yl)propanamide, SODIUM ION, ... (4 entities in total)
• Functional Keywords: protein kinase, phosphorylation, covalent inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (By similarity): P51812
• Total number of polymer chains: 1
• Total formula weight: 40304.76

Authors

Miller, R.M.,Paavilainen, V.O.,Krishnan, S.,Serafimova, I.M.,Taunton, J. (deposition date: 2013-02-28, release date: 2013-04-10, Last modification date: 2024-11-20)

Primary citation

Miller, R.M.,Paavilainen, V.O.,Krishnan, S.,Serafimova, I.M.,Taunton, J.
Electrophilic fragment-based design of reversible covalent kinase inhibitors.
J.Am.Chem.Soc., 135:5298-5301, 2013

PubMed Abstract: Fragment-based ligand design and covalent targeting of noncatalytic cysteines have been employed to develop potent and selective kinase inhibitors. Here, we combine these approaches, starting with a panel of low-molecular-weight, heteroaryl-susbstituted cyanoacrylamides, which we have previously shown to form reversible covalent bonds with cysteine thiols. Using this strategy, we identify electrophilic fragments with sufficient ligand efficiency and selectivity to serve as starting points for the first reported inhibitors of the MSK1 C-terminal kinase domain. Guided by X-ray co-crystal structures, indazole fragment 1 was elaborated to afford 12 (RMM-46), a reversible covalent inhibitor that exhibits high ligand efficiency and selectivity for MSK/RSK-family kinases. At nanomolar concentrations, 12 blocked activation of cellular MSK and RSK, as well as downstream phosphorylation of the critical transcription factor, CREB.

PubMed: 23540679
DOI: 10.1021/ja401221b

Experimental method

X-RAY DIFFRACTION (2.6 Å)