Pyrimidine Derivative Compounds as HSP90 Inhibitors in Cancer Treatment
Hsp90 is a 90 kDa ATP-dependent chaperone protein and is abundantly expressed in normal eukaryotic cells, however; Hsp90 expression in cancer cells is particularly higher than that of normal cells. Hsp90 is responsible for conformational stability, activation, maturation, and proper folding of the oncogenic client proteins for survival of cancer cells. Therefore, inhibition of Hsp90 was proposed as a cancer drug target at the beginning of the 1990s. Hsp90 N terminal domain (NTD) contains ATP binding site and chaperone activity of Hsp90 depends on ATP hydrolyses energy. Therefore, NTD is also a binding site for many known inhibitors. Pyrimidine derivatives interact with NTD, thus they inhibit binding and hydrolyzes of ATP. BII B021 (CNF2024), PU-H71, and Debio 0932 are synthetic pyrimidine ring containing new generation Hsp90 inhibitors and their anticancer activities are currently evaluated in clinical trials [3-5]. In our lab, we design and synthesize pyrimidine analogs to develop novel Hsp90 inhibitors in cancer treatment. In order to determine their anticancer potential, we perform cell culture studies with human cancer cell lines. Thermodynamic values of the interaction between the compounds and Hsp90 are determined by molecular docking studies. Furthermore, we perform luciferase refolding and ATPase inhibition assays to determine inhibition degree of Hsp90 chaperone activities. Pyrimidine derivatives are potential candidate for the development of Hsp90 inhibitors in the cancer treatment and they are underway to develop target specific anticancer agents.
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