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Small molecules targeting c-Myc oncogene: promising anti-cancer therapeutics.

Chen BJ, Wu YL, Tanaka Y, Zhang W - Int. J. Biol. Sci. (2014)

Bottom Line: Its encoded protein transduces intracellular signals to the nucleus, resulting in the regulation of cell proliferation, differentiation, and apoptosis, and has the ability to transform cells and bind chromosomal DNA. c-Myc also plays a critical role in malignant transformation.The abnormal over-expression of c-Myc is frequently observed in some tumors, including carcinomas of the breast, colon, and cervix, as well as small-cell lung cancer, osteosarcomas, glioblastomas, and myeloid leukemias, therefore making it a possible target for anticancer therapy.Such information will be of importance for the research and development of c-Myc-targeted drugs.

View Article: PubMed Central - PubMed

Affiliation: 1. Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310014, China.

ABSTRACT
The nuclear transcription factor c-Myc is a member of the Myc gene family with multiple functions and located on band q24.1 of chromosome 8. The c-Myc gene is activated by chromosomal translocation, rearrangement, and amplification. Its encoded protein transduces intracellular signals to the nucleus, resulting in the regulation of cell proliferation, differentiation, and apoptosis, and has the ability to transform cells and bind chromosomal DNA. c-Myc also plays a critical role in malignant transformation. The abnormal over-expression of c-Myc is frequently observed in some tumors, including carcinomas of the breast, colon, and cervix, as well as small-cell lung cancer, osteosarcomas, glioblastomas, and myeloid leukemias, therefore making it a possible target for anticancer therapy. In this minireview, we summarize unique characteristics of c-Myc and therapeutic strategies against cancer using small molecules targeting the oncogene, and discuss the prospects in the development of agents targeting c-Myc, in particular G-quadruplexes formed in c-Myc promoter and c-Myc/Max dimerization. Such information will be of importance for the research and development of c-Myc-targeted drugs.

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Related in: MedlinePlus

Small molecules capable of inhibiting transcriptional regulation by c-Myc. (A) Small-molecule inhibitors of c-Myc/Max dimerization; (B) small-molecule inhibitors of c-Myc/Max/DNA complex formation.
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Figure 10: Small molecules capable of inhibiting transcriptional regulation by c-Myc. (A) Small-molecule inhibitors of c-Myc/Max dimerization; (B) small-molecule inhibitors of c-Myc/Max/DNA complex formation.

Mentions: Small-molecule inhibitors of c-Myc/Max dimerization. As well as small nonpeptide molecules, which interfere with the dimerization of c-Myc/Max, a number of small-molecule inhibitors of c-Myc/Max dimerization have been discovered in the last decade 123-125. However, the design of c-Myc inhibitors is still challenging due to a lack of obvious binding sites in the c-Myc/Max interface 1. Most of the inhibitors thus far obtained were screened from chemical libraries 126. The peptide mimetic compound IIA6B17 (Fig. 10) was identified as the first small- molecule inhibitor of c-Myc/Max by Vogt and colleagues 127. Recently, using a reporter system, it was shown that IIA6B17 inhibited c-Myc transcription and interfered with c-Myc/Max dimerization 128. These high throughput screening studies pave the way of the discovery of new inhibitors of c-Myc/Max heterodimer or c-Myc/Max/DNA complex formation 123-125, 129-135. Likewise, a compound NY2267 (Fig. 10) and its structurally related derivatives were shown to strongly inhibit c-Myc/Max binding to DNA by groups of Janda and Vogt 124. NY2267, however, indiscriminately inhibits transcription mediated by c-Jun and c-Myc, since they are similar in their dimer structures 123. Because all of these small molecules so far identified require high concentrations for the inhibition of c-Myc/Max/DNA complex, it has been difficult to develop c-Myc-targeted anti-cancer therapeutics 124. Prochwnik and co-workers designed and reported seven small-molecule inhibitors of c-Myc/Max including 10058-F4 and 10074-G5 (Fig. 10) 136. They first synthesized derivatives based on the structure of 10058-F4 (IC50 = 49 μM on HL60 cells), of which 28RH-NCN-1 exhibited more potent activity in inhibiting the binding of c-Myc/Max to E-box motifs than the parent compound 10058-F4 124, 129. On the basis of the structure-activity relationship of the derivatives, pharmacophore analysis demonstrated that 31122-64-2 and 307545-04-6 inhibited the c-Myc/Max/DNA complex formation through inhibiting DNA binding of c-Myc 137. Then, it was reported that JY-3-094 (Fig. 10), an analog of 10074-G5, could interfere with the association between recombinant c-Myc and Max five-times more efficiently than the parent compound, whereas the analog has poor cell permeability. Thus, a p-carboxylic acid moiety of the analog was esterified to optimize the cellular uptake and retention. The prodrug compound JY-3-094 138 and its derivatives would warrant further optimization of small-molecule c-Myc/Max inhibitors.


Small molecules targeting c-Myc oncogene: promising anti-cancer therapeutics.

Chen BJ, Wu YL, Tanaka Y, Zhang W - Int. J. Biol. Sci. (2014)

Small molecules capable of inhibiting transcriptional regulation by c-Myc. (A) Small-molecule inhibitors of c-Myc/Max dimerization; (B) small-molecule inhibitors of c-Myc/Max/DNA complex formation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4202025&req=5

Figure 10: Small molecules capable of inhibiting transcriptional regulation by c-Myc. (A) Small-molecule inhibitors of c-Myc/Max dimerization; (B) small-molecule inhibitors of c-Myc/Max/DNA complex formation.
Mentions: Small-molecule inhibitors of c-Myc/Max dimerization. As well as small nonpeptide molecules, which interfere with the dimerization of c-Myc/Max, a number of small-molecule inhibitors of c-Myc/Max dimerization have been discovered in the last decade 123-125. However, the design of c-Myc inhibitors is still challenging due to a lack of obvious binding sites in the c-Myc/Max interface 1. Most of the inhibitors thus far obtained were screened from chemical libraries 126. The peptide mimetic compound IIA6B17 (Fig. 10) was identified as the first small- molecule inhibitor of c-Myc/Max by Vogt and colleagues 127. Recently, using a reporter system, it was shown that IIA6B17 inhibited c-Myc transcription and interfered with c-Myc/Max dimerization 128. These high throughput screening studies pave the way of the discovery of new inhibitors of c-Myc/Max heterodimer or c-Myc/Max/DNA complex formation 123-125, 129-135. Likewise, a compound NY2267 (Fig. 10) and its structurally related derivatives were shown to strongly inhibit c-Myc/Max binding to DNA by groups of Janda and Vogt 124. NY2267, however, indiscriminately inhibits transcription mediated by c-Jun and c-Myc, since they are similar in their dimer structures 123. Because all of these small molecules so far identified require high concentrations for the inhibition of c-Myc/Max/DNA complex, it has been difficult to develop c-Myc-targeted anti-cancer therapeutics 124. Prochwnik and co-workers designed and reported seven small-molecule inhibitors of c-Myc/Max including 10058-F4 and 10074-G5 (Fig. 10) 136. They first synthesized derivatives based on the structure of 10058-F4 (IC50 = 49 μM on HL60 cells), of which 28RH-NCN-1 exhibited more potent activity in inhibiting the binding of c-Myc/Max to E-box motifs than the parent compound 10058-F4 124, 129. On the basis of the structure-activity relationship of the derivatives, pharmacophore analysis demonstrated that 31122-64-2 and 307545-04-6 inhibited the c-Myc/Max/DNA complex formation through inhibiting DNA binding of c-Myc 137. Then, it was reported that JY-3-094 (Fig. 10), an analog of 10074-G5, could interfere with the association between recombinant c-Myc and Max five-times more efficiently than the parent compound, whereas the analog has poor cell permeability. Thus, a p-carboxylic acid moiety of the analog was esterified to optimize the cellular uptake and retention. The prodrug compound JY-3-094 138 and its derivatives would warrant further optimization of small-molecule c-Myc/Max inhibitors.

Bottom Line: Its encoded protein transduces intracellular signals to the nucleus, resulting in the regulation of cell proliferation, differentiation, and apoptosis, and has the ability to transform cells and bind chromosomal DNA. c-Myc also plays a critical role in malignant transformation.The abnormal over-expression of c-Myc is frequently observed in some tumors, including carcinomas of the breast, colon, and cervix, as well as small-cell lung cancer, osteosarcomas, glioblastomas, and myeloid leukemias, therefore making it a possible target for anticancer therapy.Such information will be of importance for the research and development of c-Myc-targeted drugs.

View Article: PubMed Central - PubMed

Affiliation: 1. Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310014, China.

ABSTRACT
The nuclear transcription factor c-Myc is a member of the Myc gene family with multiple functions and located on band q24.1 of chromosome 8. The c-Myc gene is activated by chromosomal translocation, rearrangement, and amplification. Its encoded protein transduces intracellular signals to the nucleus, resulting in the regulation of cell proliferation, differentiation, and apoptosis, and has the ability to transform cells and bind chromosomal DNA. c-Myc also plays a critical role in malignant transformation. The abnormal over-expression of c-Myc is frequently observed in some tumors, including carcinomas of the breast, colon, and cervix, as well as small-cell lung cancer, osteosarcomas, glioblastomas, and myeloid leukemias, therefore making it a possible target for anticancer therapy. In this minireview, we summarize unique characteristics of c-Myc and therapeutic strategies against cancer using small molecules targeting the oncogene, and discuss the prospects in the development of agents targeting c-Myc, in particular G-quadruplexes formed in c-Myc promoter and c-Myc/Max dimerization. Such information will be of importance for the research and development of c-Myc-targeted drugs.

Show MeSH
Related in: MedlinePlus