6XE4

BTK Fluorocyclopropyl amide inhibitor, Compound 25

Summary for 6XE4

• Entry DOI: 10.2210/pdb6xe4/pdb
• Descriptor: Tyrosine-protein kinase BTK, (1S,2S)-N-[2'-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-3'-(hydroxymethyl)-1-methyl-6-oxo[1,6-dihydro[3,4'-bipyridine]]-5-yl]-2-fluorocyclopropane-1-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, inflammation, drug, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 34558.39

Authors

Kiefer, J.R.,Crawford, J.J.,Lee, W.,Eigenbrot, C.,Yu, C. (deposition date: 2020-06-11, release date: 2020-07-22, Last modification date: 2024-03-06)

Primary citation

Crawford, J.J.,Lee, W.,Johnson, A.R.,Delatorre, K.J.,Chen, J.,Eigenbrot, C.,Heidmann, J.,Kakiuchi-Kiyota, S.,Katewa, A.,Kiefer, J.R.,Liu, L.,Lubach, J.W.,Misner, D.,Purkey, H.,Reif, K.,Vogt, J.,Wong, H.,Yu, C.,Young, W.B.
Stereochemical Differences in Fluorocyclopropyl Amides Enable Tuning of Btk Inhibition and Off-Target Activity.
Acs Med.Chem.Lett., 11:1588-1597, 2020

PubMed Abstract: Bruton's tyrosine kinase (Btk) is thought to play a pathogenic role in chronic immune diseases such as rheumatoid arthritis and lupus. While covalent, irreversible Btk inhibitors are approved for treatment of hematologic malignancies, they are not approved for autoimmune indications. In efforts to develop additional series of reversible Btk inhibitors for chronic immune diseases, we sought to differentiate from our clinical stage inhibitor fenebrutinib using cyclopropyl amide isosteres of the 2-aminopyridyl group to occupy the flat, lipophilic H2 pocket. While drug-like properties were retained-and in some cases improved-a safety liability in the form of hERG inhibition was observed. When a fluorocyclopropyl amide was incorporated, Btk and off-target activity was found to be stereodependent and a lead compound was identified in the form of the (,)- stereoisomer.

PubMed: 32832028
DOI: 10.1021/acsmedchemlett.0c00249

Experimental method

X-RAY DIFFRACTION (1.6 Å)