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Computational design, chemical synthesis, and biological evaluation of a novel ERK inhibitor (BL-EI001) with apoptosis-inducing mechanisms in breast cancer.

Liu B, Fu L, Zhang C, Zhang L, Zhang Y, Ouyang L, He G, Huang J - Oncotarget (2015)

Bottom Line: Extracellular signal-regulated kinase1/2 (ERK1/2) plays a crucial role in the resistance of apoptosis in carcinogenesis; however, its targeted small-molecule inhibitors still remain to be discovered.Subsequently, we synthesized some candidate ERK inhibitors, identified a novel ERK inhibitor (BL-EI001) with anti-proliferative activities, and analyzed the BL-EI001/ERK complex.Further, we found that BL-EI001 bear anti-tumor activities without remarkable toxicities, and also induced mitochondrial apoptosis by targeting ERK in vivo.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.

ABSTRACT
Extracellular signal-regulated kinase1/2 (ERK1/2) plays a crucial role in the resistance of apoptosis in carcinogenesis; however, its targeted small-molecule inhibitors still remain to be discovered. Thus, in this study, we computationally and experimentally screened a series of small-molecule inhibitors targeting ERK toward different types of human breast cancer cells. Subsequently, we synthesized some candidate ERK inhibitors, identified a novel ERK inhibitor (BL-EI001) with anti-proliferative activities, and analyzed the BL-EI001/ERK complex. Moreover, we found that BL-EI001 induced breast cancer cell apoptosis via mitochondrial pathway but independent on Ras/Raf/MEK pathway. In addition, we carried out proteomics analyses for exploring some possible BL-EI001-induced apoptotic pathways, and further found that BL-EI001-induced apoptosis affected ERK phosphorylation in breast cancer. Further, we found that BL-EI001 bear anti-tumor activities without remarkable toxicities, and also induced mitochondrial apoptosis by targeting ERK in vivo. Taken together, these results demonstrate that in silico design and experimental discovery of a synthesized small-molecule ERK inhibitor (BL-EI001)as a potential novel apoptosis-inducing drug in the treatment of breast cancer.

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Molecular dynamics (MD) simulation and anti-proliferative activities of E1 and BL-EI001(A) Comparison of molecular dynamics simulation between E1 and BL-EI001 binding to ERK1/2; (B) Comparison of anti-proliferative effects between E1 and BL-EI001 in CF-7 cells, MDA-MB468 cells and MDA-MB231 cells, respectively.
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Figure 3: Molecular dynamics (MD) simulation and anti-proliferative activities of E1 and BL-EI001(A) Comparison of molecular dynamics simulation between E1 and BL-EI001 binding to ERK1/2; (B) Comparison of anti-proliferative effects between E1 and BL-EI001 in CF-7 cells, MDA-MB468 cells and MDA-MB231 cells, respectively.

Mentions: From the results of molecular modeling, docking and dynamic stimulation of targeted compounds, we found that the nitrogen of the imidazole ring plays an important role in the interaction with the active sites. Thus, our molecular design retains the pharmacophore imidazole ring (Figure 3A). Docking of new compound BL-EI001 showed that the compound interacted with the active sites of the enzymes through hydrophobic interactions between its aromatic ring and ILE48, VAL56, ALA69 and MET125 amino-acid residues, respectively. Moreover, BL-EI001 formed two hydrogen bonds with the nitrogen of LYS71, and two Pi-Pi interactions with TYR53. (Figure 3A). Therefore, BL-EI001 might have better kinase-binding activity than E1. All the detailed information was shown (Table S4 and Table S5).


Computational design, chemical synthesis, and biological evaluation of a novel ERK inhibitor (BL-EI001) with apoptosis-inducing mechanisms in breast cancer.

Liu B, Fu L, Zhang C, Zhang L, Zhang Y, Ouyang L, He G, Huang J - Oncotarget (2015)

Molecular dynamics (MD) simulation and anti-proliferative activities of E1 and BL-EI001(A) Comparison of molecular dynamics simulation between E1 and BL-EI001 binding to ERK1/2; (B) Comparison of anti-proliferative effects between E1 and BL-EI001 in CF-7 cells, MDA-MB468 cells and MDA-MB231 cells, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466648&req=5

Figure 3: Molecular dynamics (MD) simulation and anti-proliferative activities of E1 and BL-EI001(A) Comparison of molecular dynamics simulation between E1 and BL-EI001 binding to ERK1/2; (B) Comparison of anti-proliferative effects between E1 and BL-EI001 in CF-7 cells, MDA-MB468 cells and MDA-MB231 cells, respectively.
Mentions: From the results of molecular modeling, docking and dynamic stimulation of targeted compounds, we found that the nitrogen of the imidazole ring plays an important role in the interaction with the active sites. Thus, our molecular design retains the pharmacophore imidazole ring (Figure 3A). Docking of new compound BL-EI001 showed that the compound interacted with the active sites of the enzymes through hydrophobic interactions between its aromatic ring and ILE48, VAL56, ALA69 and MET125 amino-acid residues, respectively. Moreover, BL-EI001 formed two hydrogen bonds with the nitrogen of LYS71, and two Pi-Pi interactions with TYR53. (Figure 3A). Therefore, BL-EI001 might have better kinase-binding activity than E1. All the detailed information was shown (Table S4 and Table S5).

Bottom Line: Extracellular signal-regulated kinase1/2 (ERK1/2) plays a crucial role in the resistance of apoptosis in carcinogenesis; however, its targeted small-molecule inhibitors still remain to be discovered.Subsequently, we synthesized some candidate ERK inhibitors, identified a novel ERK inhibitor (BL-EI001) with anti-proliferative activities, and analyzed the BL-EI001/ERK complex.Further, we found that BL-EI001 bear anti-tumor activities without remarkable toxicities, and also induced mitochondrial apoptosis by targeting ERK in vivo.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.

ABSTRACT
Extracellular signal-regulated kinase1/2 (ERK1/2) plays a crucial role in the resistance of apoptosis in carcinogenesis; however, its targeted small-molecule inhibitors still remain to be discovered. Thus, in this study, we computationally and experimentally screened a series of small-molecule inhibitors targeting ERK toward different types of human breast cancer cells. Subsequently, we synthesized some candidate ERK inhibitors, identified a novel ERK inhibitor (BL-EI001) with anti-proliferative activities, and analyzed the BL-EI001/ERK complex. Moreover, we found that BL-EI001 induced breast cancer cell apoptosis via mitochondrial pathway but independent on Ras/Raf/MEK pathway. In addition, we carried out proteomics analyses for exploring some possible BL-EI001-induced apoptotic pathways, and further found that BL-EI001-induced apoptosis affected ERK phosphorylation in breast cancer. Further, we found that BL-EI001 bear anti-tumor activities without remarkable toxicities, and also induced mitochondrial apoptosis by targeting ERK in vivo. Taken together, these results demonstrate that in silico design and experimental discovery of a synthesized small-molecule ERK inhibitor (BL-EI001)as a potential novel apoptosis-inducing drug in the treatment of breast cancer.

Show MeSH
Related in: MedlinePlus