6OYW

ASK1 kinase domain in complex with Compound 11

Summary for 6OYW

• Entry DOI: 10.2210/pdb6oyw/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase 5, (19S)-19-methyl-16,17,18,19-tetrahydro-8,4-(azeno)[1,2,4]triazolo[4,3-f][1,6,13]benzoxadiazacyclohexadecin-10(9H)-one, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: ask1 map3k5, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 133680.55

Authors

Marcotte, D.J. (deposition date: 2019-05-15, release date: 2019-11-27, Last modification date: 2023-10-11)

Primary citation

Himmelbauer, M.K.,Xin, Z.,Jones, J.H.,Enyedy, I.,King, K.,Marcotte, D.J.,Murugan, P.,Santoro, J.C.,Hesson, T.,Spilker, K.,Johnson, J.L.,Luzzio, M.J.,Gilfillan, R.,de Turiso, F.G.
Rational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 Inhibitors.
J.Med.Chem., 62:10740-10756, 2019

PubMed Abstract: Structural analysis of a known apoptosis signal-regulating kinase 1 (ASK1) inhibitor bound to its kinase domain led to the design and synthesis of the novel macrocyclic inhibitor (cell IC = 1.2 μM). The profile of this compound was optimized for CNS penetration following two independent strategies: a rational design approach leading to and a parallel synthesis approach leading to . Both analogs are potent ASK1 inhibitors in biochemical and cellular assays (, cell IC = 95 nM; , cell IC = 123 nM) and have moderate to low efflux ratio (ER) in an MDR1-MDCK assay (, ER = 5.2; , ER = 1.5). In vivo PK studies revealed that inhibitor had moderate CNS penetration ( = 0.17) and analog had high CNS penetration ( = 1.0).

PubMed: 31710475
DOI: 10.1021/acs.jmedchem.9b01206

Experimental method

X-RAY DIFFRACTION (2.603 Å)