BACKGROUND AND AIM: Inhibition of HSP90 is a potential strategy to treat pancreatic cancer (PC), since many client proteins of HSP90 are found to be over-expressed and/or genetically mutated in PC. These client proteins directly participate in the modulation of proliferation and aggravation of PC. Our previous works led to Y306zh as a novel and potent HSP90 inhibitor. In this study we further investigated the mode of actions of Y306zh as an anti-PC agent. MATERIALS AND METHODS: The binding affinity of Y306zh towards HSP90 was analyzed by fluorescence polarization assay. The anti-proliferative activities and molecular mechanism of Y306zh were investigated in human PC cell lines and Miapaca2 xenograft model. RESULTS: Y306zh binds tightly to the NH2-terminus of HSP90 with an IC50 of 85 nM, and this causes ATP incapable to attach to the same binding site, and disrupts HSP90-p23 association. Y306zh also induces the expression of HSP70, recruits the complex of CHIP, HSP70 and HSP90, and eventually results in the degradation of HSP90 client proteins (EGFR, AKT, C-RAF and CDK4) via proteasomal pathway. Amazingly, coincident with the molecular mechanism, Y306zh also inhibits the proliferation of PC cells through G2/M phase arrest, but appears to be totally insensitive to normal mammalian cells. Furthermore, Y306zh effectively inhibits tumor growth of Mia-paca2 xenograft mice without any obvious effect on body weight. CONCLUSIONS: Y306zh, a novel HSP90 inhibitor, interrupts ATP binding to HSP90 and disrupts HSP90-p23 interaction, and eventually inhibits the growth of PC cells.
BACKGROUND AND AIM: Inhibition of HSP90 is a potential strategy to treat pancreatic cancer (PC), since many client proteins of HSP90 are found to be over-expressed and/or genetically mutated in PC. These client proteins directly participate in the modulation of proliferation and aggravation of PC. Our previous works led to Y306zh as a novel and potent HSP90 inhibitor. In this study we further investigated the mode of actions of Y306zh as an anti-PC agent. MATERIALS AND METHODS: The binding affinity of Y306zh towards HSP90 was analyzed by fluorescence polarization assay. The anti-proliferative activities and molecular mechanism of Y306zh were investigated in human PC cell lines and Miapaca2 xenograft model. RESULTS:Y306zh binds tightly to the NH2-terminus of HSP90 with an IC50 of 85 nM, and this causes ATP incapable to attach to the same binding site, and disrupts HSP90-p23 association. Y306zh also induces the expression of HSP70, recruits the complex of CHIP, HSP70 and HSP90, and eventually results in the degradation of HSP90 client proteins (EGFR, AKT, C-RAF and CDK4) via proteasomal pathway. Amazingly, coincident with the molecular mechanism, Y306zh also inhibits the proliferation of PC cells through G2/M phase arrest, but appears to be totally insensitive to normal mammalian cells. Furthermore, Y306zh effectively inhibits tumor growth of Mia-paca2 xenograft mice without any obvious effect on body weight. CONCLUSIONS:Y306zh, a novel HSP90 inhibitor, interrupts ATP binding to HSP90 and disrupts HSP90-p23 interaction, and eventually inhibits the growth of PC cells.
Authors: Yuchen Zhang; Michael B Ware; Mohammad Y Zaidi; Amanda N Ruggieri; Brian M Olson; Hannah Komar; Matthew R Farren; Ganji Purnachandra Nagaraju; Chao Zhang; Zhengjia Chen; Juan M Sarmiento; Rafi Ahmed; Shishir K Maithel; Bassel F El-Rayes; Gregory B Lesinski Journal: Mol Cancer Ther Date: 2020-10-09 Impact factor: 6.009
Authors: Ashraf N Abdalla; Mohamed E Abdallah; Akhmed Aslam; Ammar Bader; Antonio Vassallo; Nunziatina De Tommasi; Waleed H Malki; Ahmed M Gouda; Mohammed H Mukhtar; Mahmoud Zaki El-Readi; Hamad M Alkahtani; Alaa A-M Abdel-Aziz; Adel S El-Azab Journal: Molecules Date: 2020-05-08 Impact factor: 4.411