Discovery of macrocyclic HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation. (1st September 2021)

• Record Type: Journal Article
• Authors: Yu, Wensheng; Fells, James; Clausen, Dane; Liu, Jian; Klein, Daniel J.; Christine Chung, C.; Myers, Robert W.; Wu, Jin; Wu, Guoxin; Howell, Bonnie J.; Barnard, Richard J.O.; Kozlowski, Joseph
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 47(2021)
• Publication Date: 2021-09-01
• Subjects: BTPNRALWSPISIP-FQEVSTJZSA-N -- QEADHPNYEASZRQ-PKTZIBPZSA-N -- COLQOIDCTMUDMA-AGDSBZHNSA-N -- COLQOIDCTMUDMA-VRPUFIDTSA-N -- LOLHRVDRKNBUPF-IZLXSDGUSA-N -- FVFNHWHRPHDXJO-WXQFCLCJSA-N -- WBDNRODMXIVRIW-ANAIMFLESA-N -- ZRNGPLNAAMNQKM-NLBIUBODSA-N -- XTDKCXUQMVXUHE-SFMHXDGCSA-N -- HRMSPADHUDDHPW-FTJBHMTQSA-N -- YQLXDOKERMDPOT-IZLXSDGUSA-N -- AWTXQEUYEIEIGL-QHCPKHFHSA-N -- VCIXIONCIFLLFZ-IZLXSDGUSA-N -- ONEHGRSVCWEICS-IZLXSDGUSA-N -- BMXJAODDXNZAPY-WDYNHAJCSA-N -- AMFFNKHZQUTRNE-PXJZQJOASA-N -- PLWBVDLCWWJINE-IHLOFXLRSA-N -- NHFNZFBCEYQJMW-ZWXJPIIXSA-N -- ZUOQPJWZUKPUSH-ZWXJPIIXSA-N -- BFGXDYFOPYGUQA-NDEPHWFRSA-N -- PBCOVJOHEGKJME-OWJIYDKWSA-N -- IJLNKULSDASGKT-LFQPHHBNSA-N -- SJFTZOLNFLMULZ-QSAPEBAKSA-N -- XGWNKDSIJSHVCT-IBGZPJMESA-N; HDAC inhibitor -- Macrocycle -- HIV infection -- HIV latency reactivation -- Selective HDAC inhibitor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128168
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A series of unique macrocyclic HDACs 1, 2, and 3 selective inhibitors were identified with good enzymatic activity and high selectivity over HDACs 6 and 8. These macrocyclic HDAC inhibitors used an ethyl ketone as the zinc-binding group. Compounds 25 and 26 stood out as leads due to their low double-digit nM EC50 s in the 2C4 cell-based HIV latency reactivation assay. The PK profiles of these macrocyclic HDAC inhibitors still needed improvement.