5F20

Structure of TYK2 with inhibitor 4: 3-azanyl-5-(2-methylphenyl)-7-(1-methylpyrazol-3-yl)-1~{H}-pyrazolo[4,3-c]pyridin-4-one

Summary for 5F20

• Entry DOI: 10.2210/pdb5f20/pdb
• Related: 5F1Z
• Descriptor: Non-receptor tyrosine-protein kinase TYK2, 3-azanyl-5-(2-methylphenyl)-7-(1-methylpyrazol-3-yl)-1~{H}-pyrazolo[4,3-c]pyridin-4-one (3 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 35165.21

Authors

Skene, R.J. (deposition date: 2015-12-01, release date: 2016-01-13, Last modification date: 2024-03-06)

Primary citation

Yogo, T.,Nagamiya, H.,Seto, M.,Sasaki, S.,Shih-Chung, H.,Ohba, Y.,Tokunaga, N.,Lee, G.N.,Rhim, C.Y.,Yoon, C.H.,Cho, S.Y.,Skene, R.,Yamamoto, S.,Satou, Y.,Kuno, M.,Miyazaki, T.,Nakagawa, H.,Okabe, A.,Marui, S.,Aso, K.,Yoshida, M.
Structure-Based Design and Synthesis of 3-Amino-1,5-dihydro-4H-pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors.
J.Med.Chem., 59:733-749, 2016

PubMed Abstract: We report herein the discovery and optimization of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one TYK2 inhibitors. High-throughput screening against TYK2 and JAK1-3 provided aminoindazole derivative 1 as a hit compound. Scaffold hopping of the aminoindazole core led to the discovery of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one derivative 3 as a novel chemotype of TYK2 inhibitors. Interestingly, initial SAR study suggested that this scaffold could have a vertically flipped binding mode, which prompted us to introduce a substituent at the 7-position as a moiety directed toward the solvent-exposed region. Introduction of a 1-methyl-3-pyrazolyl moiety at the 7-position resulted in a dramatic increase in TYK2 inhibitory activity, and further optimization led to the discovery of 20. Compound 20 inhibited IL-23-induced IL-22 production in a rat PD assay, as well as inhibited IL-23 signaling in human PBMC. Furthermore, 20 showed selectivity for IL-23 signaling inhibition against GM-CSF, demonstrating the unique cytokine selectivity of the novel TYK2 inhibitor.

PubMed: 26701356
DOI: 10.1021/acs.jmedchem.5b01857

Experimental method

X-RAY DIFFRACTION (2.91 Å)