Abstract 2257: Thailanstatins: New pre-mRNA splicing inhibitors and potent antiproliferative agents discovered from Burkholderia Thailandensis MSMB43.

Abstract

Abstract Natural products have been traditionally sought from actinomycetes, filamentous fungi and medicinal plants. Gram-negative bacterial species, such as Burkholderia, Chromobacterium, Lysobacter, Pseudomonas and Xenorhabdus, however, have recently captured attention as new sources of diverse bioactive natural products. Mining the genome sequence of B. thailandensis MSMB43 revealed a cryptic biosynthetic gene cluster highly resembling that of FR901,464, a prototype pre-mRNA splicing inhibitor produced by Pseudomonas sp. No. 2663. Transcriptioal analysis identified a cultivation condition in which a representive gene of the cryptic gene cluster is adequately expressed. Consequently, three new compounds, thailanstatins A, B and C, were isolated from the fermentation broth of B. thailandensis MSMB43 through natural product chemistry. Thailanstatins belong to the FR901,464-family of microbial products biosynthesized by a hybrid polyketide synthease-nonribosomal peptide synthetase pathway. They have an oveall structural similarity with FR901,464, but feature an extra acetic acid unit which endows the compouds with a significantly higher stability than FR901,464 under physiologically relevant conditions. In vitro assays showed that thailanstatins inhibit pre-mRNA splicing as potently as FR901,464, with half-maximal inhibitory concentrations in the single to sub μM range, causing pre-mRNA to accumulate and preventing the production of mRNA and splicing intermediates. In vitro cell culture assays indicated that thailanstatins also possess potent antiproliferative activities in representative human cancer cell lines, with half-maximal growth inhibitory concentrations in the single nM range (Table 1). This work provides new chemical entities for research and development, and validates the Burkholderia species as an exciting new source of bioactive natural products. Table 1.Antiproliferative activities of compounds in human cancer cell lines (GI50 in nM).CompoundDU-145 (prostate cancer)H232A (non-small cell lung cancer)MDA-MB235 (triple-negative breast cancer)SKOV-3 (ovarian cancer)Thailanstatin A1.11±0.022.26±0.172.58±0.112.69±0.37Thailanstatin B3.00±0.922.50±0.066.22±1.674.94±1.76Thailanstatin C2.98±0.903.67±0.538.82±2.205.57±2.01FR901,4641.05±0.021.94±0.242.10±0.191.06±0.01 Citation Format: Xiangyang Liu, Sreya Biswas, Michael G. Berg, Christopher M. Antapli, Feng Xie, Qi Wang, Man-Cheng Tang, Gong-Li Tang, Lixin Zhang, Gideon Dreyfuss, Yi-Qiang Cheng. Thailanstatins: New pre-mRNA splicing inhibitors and potent antiproliferative agents discovered from Burkholderia Thailandensis MSMB43. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2257. doi:10.1158/1538-7445.AM2013-2257