8GMN

Crystal structure of human C1s in complex with inhibitor

Summary for 8GMN

• Entry DOI: 10.2210/pdb8gmn/pdb
• Descriptor: Complement C1s subcomponent, [4-(1-aminophthalazin-6-yl)piperazin-1-yl](2-methylphenyl)methanone, SULFATE ION, ... (4 entities in total)
• Functional Keywords: complement c1s hydrolase. protease serine protease, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 164674.72

Authors

Dougan, D.R.,Lane, W. (deposition date: 2023-03-26, release date: 2023-05-17, Last modification date: 2024-11-20)

Primary citation

Ikeda, Z.,Kamei, T.,Sasaki, Y.,Reynolds, M.,Sakai, N.,Yoshikawa, M.,Tawada, M.,Morishita, N.,Dougan, D.R.,Chen, C.H.,Levin, I.,Zou, H.,Kuno, M.,Arimura, N.,Kikukawa, Y.,Kondo, M.,Tohyama, K.,Sato, K.
Discovery of a Novel Series of Potent, Selective, Orally Available, and Brain-Penetrable C1s Inhibitors for Modulation of the Complement Pathway.
J.Med.Chem., 66:6354-6371, 2023

PubMed Abstract: A novel series of non-amidine-based C1s inhibitors have been explored. Starting from high-throughput screening hit , isoquinoline was replaced with 1-aminophthalazine to enhance C1s inhibitory activity while exhibiting good selectivity against other serine proteases. We first disclose a crystal structure of a complex of C1s and a small-molecule inhibitor (), which guided structure-based optimization around the S2 and S3 sites to further enhance C1s inhibitory activity by over 300-fold. Improvement of membrane permeability by incorporation of fluorine at the 8-position of 1-aminophthalazine led to identification of as a potent, selective, orally available, and brain-penetrable C1s inhibitor. significantly inhibited membrane attack complex formation induced by human serum in a dose-dependent manner in an in vitro assay system, proving that selective C1s inhibition blocked the classical complement pathway effectively. As a result, emerged as a valuable tool compound for both in vitro and in vivo assessment.

PubMed: 37120845
DOI: 10.1021/acs.jmedchem.3c00348

Experimental method

X-RAY DIFFRACTION (2.6 Å)