Hall Jessica A, Forsberg Leah K, Blagg Brian S J
Department of Medicinal Chemistry, The University Of Kansas, 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, KS 66045, USA.
Future Med Chem. 2014 Sep;6(14):1587-605. doi: 10.4155/fmc.14.89.
Hsp90 is responsible for the conformational maturation of newly synthesized polypeptides (client proteins) and the re-maturation of denatured proteins via the Hsp90 chaperone cycle. Inhibition of the Hsp90 N-terminus has emerged as a clinically relevant strategy for anticancer chemotherapeutics due to the involvement of clients in a variety of oncogenic pathways. Several immunophilins, co-chaperones and partner proteins are also necessary for Hsp90 chaperoning activity. Alternative strategies to inhibit Hsp90 function include disruption of the C-terminal dimerization domain and the Hsp90 heteroprotein complex. C-terminal inhibitors and Hsp90 co-chaperone disruptors prevent cancer cell proliferation similar to N-terminal inhibitors and destabilize client proteins without induction of heat shock proteins. Herein, current Hsp90 inhibitors, the chaperone cycle, and regulation of this cycle will be discussed.
热休克蛋白90（Hsp90）负责新合成多肽（客户蛋白）的构象成熟以及通过Hsp90伴侣循环使变性蛋白重新成熟。由于客户蛋白参与多种致癌途径，抑制Hsp90 N端已成为抗癌化疗的一种临床相关策略。几种亲免蛋白、共伴侣蛋白和伴侣蛋白对于Hsp90的伴侣活性也是必需的。抑制Hsp90功能的替代策略包括破坏C端二聚化结构域和Hsp90异源蛋白复合物。C端抑制剂和Hsp90共伴侣破坏剂与N端抑制剂类似，可阻止癌细胞增殖，并使客户蛋白不稳定，而不会诱导热休克蛋白。本文将讨论当前的Hsp90抑制剂、伴侣循环及其对该循环的调控。
