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| Type |
Poster Presentation |
| Area |
Life Chemistry |
| Room No. |
Exhibition Hall 2 |
| Time |
4월 19일 (금요일) 11:00~12:30 |
| Code |
LIFE.P-383 |
| Subject |
Targeting NHR2 domain of AML1-ETO via bivalent peptides. |
| Authors |
Daseul Ko, Hyun-Suk Lim*
Department of Chemistry, Pohang University of Science and Technology, Korea
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| Abstract |
AML (Acute Myeloid Leukemia), an aggressive cancer of the myeloid cells, makes up 32 % of all adult leukemia patients. One of the representative karyotypic abnormality for AMLs patients is translocation t(8;21)(q22;q22), which combines AML1 gene in chromosome 21 and ETO gene in chromosome 8. Expression of AML1-ETO fusionprotein, expressed through a result of the translocation t(8;21), is closely related to AMLs development. Unlike normal AML1, AML1-ETO act as a transcription factor that inhibits the transcription of hematopoiesis-related genes and blocks hematopoietic differentiation. As a result of the alternation of transcription activity, AML1-ETO leads leukemogenesis. Among the five domains of AML1-ETO, NHR2 domain plays an important role in protein-protein interaction to E protein families. Several studies approved that the inhibition of functions of NHR2 domain blocks leukemogenesis and inhibits proliferation of t(8;21) AML cancer cells. These studies shows that targeting NHR2 domain could be an interesting therapeutic strategy for modulating AMLs. Despite the importance of NHR2 domain, however, no inhibitors have been developed for controlling the PPI between NHR2 domain and E proteins. Here, we designed inhibitor for NHR2 domain to control protein-protein interaction between NHR2 domain and E proteins. The binding affinity between NHR2 domain and short N2B peptide, NHR2 binding domain of E protein, has been reported previously, however, the binding affinity was quite low (KD = 0.38 mM). Starting from the crystal structure, we designed NHR2 domain targeting bivalent peptides which various length of linker to obtain the maximal binding. Designed bivalent peptides showed 10-fold improved binding affinity compare to the monovalent N2B peptide. Designed peptides will serve as a useful chemical modulator to inhibit the function of NHR2 domain. And it will provides a promising starting point for the development of a novel class of therapeutic agents for AMLs.
Reference
[1] Nature, 2013, 500 (7460), pp 93-97.
[2] ACS Med. Chem., 2013, 4 (3), pp 344–348.
[3] J. Am. Chem. Soc, 2006, 128 (26), pp 8615-8625. |
| E-mail |
aworlyuki@postech.ac.kr |
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123rd General Meeting of the KCS