Bioorg Med Chem Lett. 2022 Dec 19. pii: S0960-894X(22)00587-X. [Epub ahead of print]
129111
Heat shock protein 90 (Hsp90) is a dynamic protein which serves to ensure proper folding of nascent client proteins, regulate transcriptional responses to environmental stress and guide misfolded and damaged proteins to destruction via ubiquitin proteasome pathway. Recent advances in the field of Hsp90 have been made through development of isoform selective inhibitors, Hsp90 C-terminal inhibitors and disruption of protein-protein interactions. These approaches have led to alleviation of adverse off-target effects caused by pan-inhibition of Hsp90 using N-terminal inhibitors. In this review, we provide an overview of relevant advances on targeting the Hsp90 C-terminal Domain (CTD) and the development of Hsp90 C-terminal inhibitors (CTIs) since 2015. The proper functioning and folding of proteins is necessary for cell survival.1 Cellular stresses such as acidosis, exposure to toxins, viruses, DNA damage, metabolic and oxidative stress, and/or hypoxia lead to the disruption of proteostasis, and can result in a lethal outcome. To maintain proteostasis upon exposure to cellular stresses, cells induce the expression of molecular chaperones such as the heat shock proteins.2 This protein family is divided based on molecular weight and includes Hsp27, Hsp40, Hsp60, Hsp70, Hsp90, as well as other larger members, each of which plays a unique role during the protein folding cycle.3 The 90kDa Heat Shock Proteins (Hsp90) are ubiquitous and highly-conserved molecular chaperones that are responsible for the activation, stabilization and maturation of ∼400 client protein substrates. Hsp90 comprises ∼1-2% of all cellular proteins, however, Hsp90 expression is elevated to ∼4-6% of total protein content in cancer cells. Hsp90 is a homodimer with each monomer consisting of three components; an ATP-binding N-terminal domain (NTD), a middle domain (MD) wherein protein-protein interactions occur, and a C-terminal domain (CTD) that is responsible for dimerization.4 The CTD contains a nucleotide binding site that allosterically modulates ATPase activity within the NTD.5 The CTD also possesses a conserved Met-Glu-Glu-Val-Asp (MEEVD) sequence at the terminus to provide interactions with co-chaperones that contain a tetratricopeptide-containing repeat (TPR).6 These interactions with co-chaperones are vital for the regulation and progression of the Hsp90 protein folding cycle.
Keywords: Anti-cancer; Chaperones; Hasp90; Neuroprotective; Novobiocin