Heat Shock Protein and Cancer Based Therapies
Tumor cells have higher metabolic rates compared to normal cells. Biochemical reactions require properly folded proteins to perform pathway specific functions. Nascent substrate proteins specially signaling and cell cycle molecules must be folded in short
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stract Introduction Tumor cells have higher metabolic rates compared to normal cells. Biochemical reactions require properly folded proteins to perform pathway specific functions. Nascent substrate proteins specially signaling and cell cycle molecules must be folded in shorter times. Tumor cells overexpress Heat Shock Proteins (HSP) to help client proteins folding. Most of the HSP have anti-apoptotic functions and help tumor cell survival. HSP90 and HSP70 are at the center of heat shock response mechanism and drug designers target HSP to inhibit these two essential functions to drive tumor cells to apoptosis. Methods Small molecule inhibitors inhibited HSP by competitive inhibition with nucleotides, by perturbing protein-protein interactions through interface inhibitors, and by binding to allosteric sites and disrupting conformational changes. Major databases (Pubmed, Scopus, and WOS) were surveyed with the keywords “Hsp90”, “Hsp70”, “anti-cancer agent”, and “inhibitor”.
L. Tutar Faculty of Science and Letters, Department of Molecular Biology and Genetics, Kırşehir Ahi Evran University, Kırşehir, Turkey E. N. Yenilmez Tunoglu Turkey Health Sciences Institutes, Division of Molecular Medicine, University of Health Sciences, İstanbul, Turkey B. Yeman Kiyak Turkey, Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, İstanbul, Turkey Y. Tutar (*) Turkey Health Sciences Institutes, Division of Molecular Medicine, University of Health Sciences, İstanbul, Turkey Turkey, Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, İstanbul, Turkey e-mail: [email protected] © Springer Nature Switzerland AG 2020 A. A. Asea, P. Kaur (eds.), Heat Shock Proteins, https://doi.org/10.1007/7515_2020_14
L. Tutar et al.
Results One major challenge for HSP inhibitor design is complementing function of this protein family. HSP70 can complement HSP90 function or alternatively, redundant isoforms may complement each other. Further, different isoforms have similar structures and inhibition of specific HSP may be difficult. In spite of these critical problems, several agents are designed for HSP inhibition. These inhibitors and their derivatives provide templates for drug design. Conclusions HSP90 inhibitors have been widely studied and displayed promising anticancer activity for variety of cancer. This work explains current efforts on cancer treatment through HSP inhibition mechanisms. Keywords DNAJ · Heat shock protein · HSP60 · HSP70 · HSP90 · Nucleotide exchange factor
Abbreviations Hsc HSP Hsp70 NEF SBD sHSP
Hsp70 constitutive form heat shock proteins Hsp70 inductive form nucleotide exchange factor substrate binding domain small HSP
1 Introduction Drug targeting through key targets can modulate biochemical functions. HSP family control protein homeostasis and function therefore, manipulation of HSP related pathways are interest to drug designers. However, redundant isoforms and c
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