The objective of the first part of this study was to investigate the Hsp90 protein possible activ ity of a novel quinazoline Her2/ EGFR inhibitor (Co mpound No. 1: 4-(2-(4-Oxo-2-thio xo-1,4-d ihydroquinazolin-3(2H)yl)ethyl)benzenesulfonamide) p reviously synthesized by a collaborating group. Heat shock protein 90 (Hsp90) has a central ro le in regulation of several client proteins involved in cancers [1,2]. Several Hsp90 inhibitors of the natural or synthetic origin d isplayed potent anticancer activity [3,4]. Accordingly, Hsp90 emerged as an attractive target in the design of anticancer agents. To evaluate the binding mode of compound No. 1 into the ATPase site of Hsp90, a co mparative mo lecular docking study was performed using AutoDock 4.2. The results of this studywas compared with that of the co-crystallized ligand (ATI-13387X, Onalespib). The energy minimization process of the chemical structures of No. 1 was done following our previous report [5]. The results of the docking study revealed that No. 1 fit n icely into the ATPase site, and it displayed a binding free energy (Gb) of-7.21 kcal/ mo l and inhibition constant (Ki) of 5.19 µM to Hsp90, co mpared to Gb of-7.90 kcal/ mol and Ki of 1.62 µM for ATI-13387X. Furthermore, to confirm this result, the surface plasmon resonance (SPR) was devised to test the Hsp90 inhibition activity of No.1, wh ich was 51 nM co mpared to Rad icico l and 17AA G (1.8 nM, and 360 nM; respectively). Overall, co mpound No. 1 exh ibited pro mising Hsp90 inhib iting activity. The second part of the study focused on the effect of No. 1, Dinaciclib and their co mbinationsin HL-60 leukemia cells. The comb ination showed synergistic EGFR inhib ition effect in HL-60 cells. Moreover, No. 1, Dinaciclib and their combination caused a significant increase in the Sub-G1 co mpared to control and doxorubicin (24h), at the expense of S and G2/M cell cycle phases. Cyclin D3, was consequently inhibited by each of the two drugs, and synergistically by their comb ination in HL-60 cells. Furthermore, each of the two drugs downregulated Survivin, wh ich was synergistically inhib ited by the co mbination. In conclusion, co mpound No.1, Dinaciclib and their comb inations showed synergestic EGFR inhibit ion; and pro-apoptoticeffect in HL-60 cells.This project was funded by the deanship of scientific research, Umm Alqura University, KSA (DSR: 15-M ED-3-1-0060). Keywords: Novel quinazoline EGFR inhi bi tor, Hs p90 protein, Leukemi a cells.

A Novel Quinazoline Inhibits Hsp90 Protein, EGFR and Induces Apoptosis in Leukemia Cells

Antonio Vassallo;
2019

Abstract

The objective of the first part of this study was to investigate the Hsp90 protein possible activ ity of a novel quinazoline Her2/ EGFR inhibitor (Co mpound No. 1: 4-(2-(4-Oxo-2-thio xo-1,4-d ihydroquinazolin-3(2H)yl)ethyl)benzenesulfonamide) p reviously synthesized by a collaborating group. Heat shock protein 90 (Hsp90) has a central ro le in regulation of several client proteins involved in cancers [1,2]. Several Hsp90 inhibitors of the natural or synthetic origin d isplayed potent anticancer activity [3,4]. Accordingly, Hsp90 emerged as an attractive target in the design of anticancer agents. To evaluate the binding mode of compound No. 1 into the ATPase site of Hsp90, a co mparative mo lecular docking study was performed using AutoDock 4.2. The results of this studywas compared with that of the co-crystallized ligand (ATI-13387X, Onalespib). The energy minimization process of the chemical structures of No. 1 was done following our previous report [5]. The results of the docking study revealed that No. 1 fit n icely into the ATPase site, and it displayed a binding free energy (Gb) of-7.21 kcal/ mo l and inhibition constant (Ki) of 5.19 µM to Hsp90, co mpared to Gb of-7.90 kcal/ mol and Ki of 1.62 µM for ATI-13387X. Furthermore, to confirm this result, the surface plasmon resonance (SPR) was devised to test the Hsp90 inhibition activity of No.1, wh ich was 51 nM co mpared to Rad icico l and 17AA G (1.8 nM, and 360 nM; respectively). Overall, co mpound No. 1 exh ibited pro mising Hsp90 inhib iting activity. The second part of the study focused on the effect of No. 1, Dinaciclib and their co mbinationsin HL-60 leukemia cells. The comb ination showed synergistic EGFR inhib ition effect in HL-60 cells. Moreover, No. 1, Dinaciclib and their combination caused a significant increase in the Sub-G1 co mpared to control and doxorubicin (24h), at the expense of S and G2/M cell cycle phases. Cyclin D3, was consequently inhibited by each of the two drugs, and synergistically by their comb ination in HL-60 cells. Furthermore, each of the two drugs downregulated Survivin, wh ich was synergistically inhib ited by the co mbination. In conclusion, co mpound No.1, Dinaciclib and their comb inations showed synergestic EGFR inhibit ion; and pro-apoptoticeffect in HL-60 cells.This project was funded by the deanship of scientific research, Umm Alqura University, KSA (DSR: 15-M ED-3-1-0060). Keywords: Novel quinazoline EGFR inhi bi tor, Hs p90 protein, Leukemi a cells.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11563/145202
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