7KSI
Thiophenyl-Pyrazolourea Derivatives as Potent, Brian Penetrant, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors
Summary for 7KSI
| Entry DOI | 10.2210/pdb7ksi/pdb |
| Descriptor | Mitogen-activated protein kinase 10, 4-(4-{[(2-chloro-6-fluorophenyl)carbamoyl]amino}-1H-pyrazol-1-yl)-5-methyl-N-(oxetan-3-yl)thiophene-2-carboxamide (3 entities in total) |
| Functional Keywords | jnk3, kinase inhibitor, alzheimer disease, pyrazolourea, neurodegeneration, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 53099.22 |
| Authors | Park, H. (deposition date: 2020-11-23, release date: 2021-03-03, Last modification date: 2023-10-18) |
| Primary citation | Feng, Y.,Park, H.,Bauer, L.,Ryu, J.C.,Yoon, S.O. Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors. Acs Med.Chem.Lett., 12:24-29, 2021 Cited by PubMed Abstract: Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with oral bioavailability and brain penetrant capability were developed. Inhibitor was a potent and isoform selective JNK3 inhibitor (IC = 35 nM), had significant inhibition to only JNK3 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in human liver microsome ( = 66 min) and a clean CYP-450 inhibition profile, and was orally bioavailable and brain penetrant. Moreover, cocrystal structures of compounds and in human JNK3 were solved at 1.84 Å, which showed that these JNK3 isoform selective inhibitors bound to the ATP pocket, had interactions in both hydrophobic pocket-I and hydrophobic pocket-II. PubMed: 33488960DOI: 10.1021/acsmedchemlett.0c00533 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.726 Å) |
Structure validation
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