Heat shock proteins (Hsps) are important biological targets in th next generation of cancer treatments. Hsps play vital roles in protein hemostasis pathways (proper folding and stabilization of nascent proteins, inhibition of protein aggregation, degradation of aggregated proteins, signal transduction and protein translocation) in eukaryotic and prokaryotic cells. Hsps are found in different cellular compartments and their expression level is increased in response to cellular and external stress factors (tumorogenesis, UV light, hypoxia, oxidative, infection, stress, fever, temperature variation) [1]. Therefore, pathogenesis of diseases is related with expression level of Hsps. Hsps are over-expressed in cancer cells, and especially, Hsp27, Hsp70 and Hsp90 are involved in all phases of tumorogenesis (apoptosis, metastases, angiogenesis, invasion, and cell differentiation). Hsp27, Hsp70 and Hsp90 ensure stabilization, activation and proper folding of the oncogenic proteins in cancer cells. Therefore, inhibition of Hsps emerged as a significant therapeutic strategy for targeted cancer treatments. Inhibition of Hsp90 chaperone activity has been significant drug- targeted for the past 30 years in cancer treatment. Now, approximately 20 different compounds are in clinical phase studies [2,3]. Clinical and pre-clinical studies demonstrated that inhibition of Hsp90 activity is not enough by itself. Inhibition of Hsp90 triggers expression of Hsp70 and complements inhibited Hsp90 chaperone activity. Moreover, Hsp27 controls and regulates key points of the apoptotic pathway in cancer cells. Therefore, in addition to Hsp90 inhibition, blocking of Hsp70 and Hsp27 chaperone activities is a remarkable therapeutic strategy for cancer treatment [4].
In our lab, we designed and synthesized novel pyrimidine and coumarin derivatives as Hsp90 inhibitors. Pyrimidine analogs interrupted Hsp90 ATP hydrolysis process through disrupting N terminal domain (NTD) conformational change [5]. Coumarin derivatives inhibited C terminal domain (CTD) of Hsp90, and blocked dimerization process [6].
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the financial support received from the Scientific and Technological Research Council of Turkey, TÜBİTAK (Grant # 114Z365).
REFERENCES
[1] Tutar, L.; Tutar, Y. Heat shock proteins; an overview. Curr. Pharm.Biotechnol., 2010, 11, 216-222.
[2] Ozgur, A.; Tutar, Y. Heat shock protein 90 inhibitors in oncology. Curr.Proteo., 2014, 11, 2-16.
[3] Ozgur, A.; Tutar, Y. Heat Shock Protein 90 Inhibition in Cancer Drug Discovery: From Chemistry to Futural Clinical Applications. Anticancer Agents Med. Chem., 2016, 16, 280-90.
[4] Tutar, Y. Inhibition of Heat Shock Protein 70 and 90 (Hsp70 And Hsp90) in Target
Specific Cancer Treatment. Adv. Tech. Biol. Med., 2015, 3.
[5] Koca, İ.; Ozgur, A.; Er, M.; Gümüş, M.; Coşkun, K.A.; Tutar, Y. Design and synthesis of pyrimidinyl acyl thioureas as novel Hsp90 inhibitors in invasive ductal breast cancer and its bone metastasis. Eur. J. Med. Chem., 2016, 122, 280-290.
[6] Koca İ, Gümüş M, Özgür A, Dişli A, Tutar Y. A novel approach to inhibit heat shock response as anticancer strategy by coumarine compounds containing thiazole skeleton. Anticancer Agents Med. Chem., 2015, 15, 916-930.
