In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1640-1640
Abstract:
Lysophosphatidic acid acyltransferase (LPAAT-β), a phosphatidic acid (PA)-generating enzyme, plays an essential role in triglyceride synthesis. A less familiar role for LPAAT-β is that of a regulator of cell growth and differentiation by means of the function of its product, PA, which plays a vital role in the activation of key signal transduction proteins including Raf, PKC-ζ and mTOR. It is in this role that LPAAT-β presents as a potential therapeutic target in cancer. Accordingly, we developed a library of small molecule inhibitors of LPAAT-β with nanomolar activity against LPAAT-β enzyme activity in vitro (2012 Annual Meeting, Abstract #2470). We have now performed additional SAR and lead optimization to produce a potent small molecule that inhibits proliferation, mTOR signaling pathways, and total cellular PA levels at low micromolar concentrations. The lead compound also inhibits anchorage-independent growth of pancreatic cancer cell lines at nanomolar concentrations. This compound demonstrates effects on cellular signaling that are similar to the effects of LPAAT-β siRNA. Citation Format: Michelle A. Blaskovich, Yunting Luo, Yiyu Ge, Saïd M. Sebti, Harshani R. Lawrence, Nicholas J. Lawrence, Gregory M. Springett. A novel small molecule inhibitor of lysophosphatidic acid acyltransferase-beta inhibits pancreatic cancer cell proliferation and mTOR signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1640. doi:10.1158/1538-7445.AM2014-1640
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-1640
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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