Design and testing of novel anti-cancer agents targeting secretory pathway calcium ATPase

Lin, Jennifer H., Peters, Amelia A., Monteith, Gregory R., Groundwater, Paul W. and Hibbs, David E. (2013). Design and testing of novel anti-cancer agents targeting secretory pathway calcium ATPase. In: ASCEPT 2013: Abstracts. ASCEPT 2013: Annual Scientific Meeting, Melbourne, VIC, Australia, (125-125). 1-4 December, 2013.

Author Lin, Jennifer H.
Peters, Amelia A.
Monteith, Gregory R.
Groundwater, Paul W.
Hibbs, David E.
Title of paper Design and testing of novel anti-cancer agents targeting secretory pathway calcium ATPase
Conference name ASCEPT 2013: Annual Scientific Meeting
Conference location Melbourne, VIC, Australia
Conference dates 1-4 December, 2013
Proceedings title ASCEPT 2013: Abstracts
Place of Publication Hamilton Central QLD, Australia
Publisher Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists
Publication Year 2013
Sub-type Published abstract
Open Access Status
Start page 125
End page 125
Total pages 1
Language eng
Formatted Abstract/Summary
Introduction. Basal-like breast cancer has the poorest prognosis of all known breast cancer subtypes and there are no effective targeted treatment agents currently available. Secretory pathway calcium ATPase (SPCA) has been found to relate to tumour growth in basal-like breast cancer and may be a potential drug target. Aims. To design and test novel chemical compounds that will inhibit SPCA.

Methods. In silico molecular modelling was used to generate an SPCA model based on its 1d isoform, and four potential drug binding sites were found. This was followed by a rational drug design process and compounds selected on predicted binding affinity were tested via fluorometric imaging plate reader (FLIPR) to measure intracellular calcium level in the MDA-MB-231 cell line. A similar process was used to design a compound inhibiting sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA).

Results. One of the compounds tested in the basal-like breast cancer cells might be a weak SPCA inhibitor. The compound designed to target SPCA1d demonstrated modest effects on intracellular calcium compared to the control compound cyclopiazonic acid (CPA). A second compound designed to target SERCA also showed minimal effects when compared to CPA.

Discussion. Two novel compounds were designed and tested in the breast cancer cell line. The results obtained from FLIPR indicated that both compounds were likely weak inhibitors of both SPCA1d and SERCA. To improve the activity of SPCA1 inhibitors, it may be necessary to use similar core structural motifs present in CPA.
Q-Index Code EX
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Conference Paper
Collection: School of Pharmacy Publications
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Created: Wed, 27 Aug 2014, 11:20:48 EST by Charna Kovacevic on behalf of School of Pharmacy