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Title: Design, synthesis and evaluation of S100A4 protein inhibitors
Author: Liu, Yidong
ISNI:       0000 0004 7228 8234
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2015
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S100A4 is a 101-amino acid protein belong to a largest sub group of EF-hand calcium binding proteins, and has been described as having both intracellular and extracellular functions. Human S100A4 is the best characterized member of the S100 protein family in terms of its role in cancer and metastasis formation. Overexpression of S100A4 has been observed in several metastatic cancers. It is recognized that an increased level of S100A4 expression correlates with a high incidence of metastasis and poor prognosis for cancer patients. Therefore S100A4 is regarded as a practical target for cancer treatment. The work of investigating S100A4 inhibitors is presented in this thesis. Using the fluorescence resonance energy transfer (FRET) method, a biochemistry assay for monitoring the binding between S100A4 and two of its targets, annexin A2 and myosin IIA, was successfully established. By using this FRET assay, 89 3-hydroxy-1H-pyrrol-2(51-1)-one compounds were screened against the binding of S 100A4 to an annexin A2 (1-14) peptide. 68 compounds were found to be active to inhibit the interaction, exhibiting a different degree of potency. A structure activity relationship (SAR) of all active compounds was established, supported by the predicted binding poses from docking studies. Guided by these SAR conclusions, 13 novel compounds were designed and synthesized based on the 3-hydroxy-1H-pyrrol-2(5H)-one scaffold in order to find better S100A4 inhibitors as well as to further confirm the SAR study. Activities of these new chemicals against both S100A4-annexin A2 complex and S100A10-annexin A2 complex were examined showing very interesting results of different potencies against the two different targets. Docking studies revealed an alternative binding pose, which could be used to explain the potencies and selectivity of novel 3-hydroxy-1H-pyrrol-2(51)-one inhibitors. Two compounds with high S100A4 selectivity were capable of inhibiting the interaction of S100A4 with surface annexin A2 of MDA-231 breast cancer cells In conclusion, this work for the first time identified a series of 3- hydroxy-1H-pyrrol-2(5H)-one compounds as S100A4-annexin A2 inhibitors. The effectiveness of inhibiting S100A4-annexin A2 interaction on cell surface has been proved by selected compounds. As S100A4 plays an important role in cancer metastasis, the results described in this thesis, including the screening method, compounds synthesizing and docking studies, are very meaningful and important to fully understand the specific role of S100A4 in cancer progression in future. This could be a promising start for the development of new cancer treatments.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available