title: Computer-aided identification of new histone deacetylase 6 selective inhibitor with anti-sepsis activity.
abstract: Histone deacetylase (HDAC) inhibitors have been recognized as promising approaches to the treatment of various human diseases including cancer, inflammation, neurodegenerative diseases, and metabolic disorders. Several pan-HDAC inhibitors are currently approved only as anticancer drugs. Interestingly, SAHA (vorinostat), one of clinically available pan-HDAC inhibitors, shows an anti-inflammatory effect at concentrations lower than those required for inhibition of tumor cell growth. It was also reported that HDAC6 selective inhibitor tubastatin A has anti-inflammatory and anti-rheumatic effect. In our efforts to develop novel HDAC inhibitors, we rationally designed various HDAC inhibitors based on the structures of two hit compounds identified by virtual screening of chemical database. Among them, 9a ((E)-N-hydroxy-4-(2-styrylthiazol-4-yl)butanamide) was identified as a HDAC6 selective inhibitor (IC50 values of 0.199 μM for HDAC6 versus 13.8 μM for HDAC1), and it did not show significant cytotoxicity against HeLa cells. In vivo biological evaluation of 9a was conducted on a lipopolysaccharide (LPS)-induced mouse model of sepsis. The compound 9a significantly improved 40% survival rate (P = 0.0483), and suppressed the LPS-induced increase of TNF-α and IL-6 mRNA expression in the liver of mice. Our study identified novel HDAC6 selective inhibitor 9a, which may serve as a potential lead for the development of anti-inflammatory or anti-sepsis agents.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Jakyung
authors.initials: J
authors.lastname: Yoo
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: So-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Dohyun
authors.initials: D
authors.lastname: Son
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Heewon
authors.initials: H
authors.lastname: Seo
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Seung Yeop
authors.initials: SY
authors.lastname: Baek
authors.affiliation: SK Biopharmaceuticals Co. Ltd., 325 Exporo Yuseong-gu, Daejeon 305-712, Republic of Korea.
authors.forename: Cheol-Young
authors.initials: CY
authors.lastname: Maeng
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Changsik
authors.initials: C
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: In Su
authors.initials: IS
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Jung
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Sun-Mee
authors.initials: SM
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea. Electronic address: hyunju85@skku.edu.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D017076:Computer-Aided Design; D015195:Drug Design; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D018805:Sepsis / Q000188:drug therapy*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases
keywords: Anti-sepsis; Computer-aided drug design; HDAC6 selective inhibitor