免疫蛋白酶体低分子量多肽2（LMP2）亚基高选择性抑制剂的发现。
Discovery of Highly Selective Inhibitors of the Immunoproteasome Low Molecular Mass Polypeptide 2 (LMP2) Subunit.
作者信息
Johnson Henry W B, Anderl Janet L, Bradley Erin K, Bui John, Jones Jeffrey, Arastu-Kapur Shirin, Kelly Lisa M, Lowe Eric, Moebius David C, Muchamuel Tony, Kirk Christopher, Wang Zhengping, McMinn Dustin
机构信息
Kezar Life Sciences, 300 Utah Avenue, Suite 105, South San Francisco, California 94080, United States.
Onyx Pharmaceuticals, An Amgen Subsidiary, 249 East Grand Avenue, South San Francisco, California 94080, United States.
出版信息
ACS Med Chem Lett. 2017 Mar 9;8(4):413-417. doi: 10.1021/acsmedchemlett.6b00496. eCollection 2017 Apr 13.
Abstract
Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition . Screening a focused library of epoxyketones revealed a series of potent dipeptides that were optimized to provide the highly selective inhibitor ().
摘要
基于硼替佐米（万珂）和卡非佐米（凯洛斯）的成功，设计针对免疫蛋白酶体中特定亚基的下一代抑制剂对于自身免疫性疾病的治疗具有重要意义。免疫蛋白酶体中有三个催化亚基（低分子量多肽-7、-2和多催化内肽酶复合物亚基-1；LMP7、LMP2和MECL-1），并且开展了一项研究以设计一种具有足够特性以实现持续抑制的强效且选择性的LMP2抑制剂。筛选一个聚焦的环氧酮文库揭示了一系列强效二肽，这些二肽经过优化以提供高选择性抑制剂（）。
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