Chemical Synthesis and Antitumor Activity of FR901464

Precursor messenger RNA (pre-mRNA) splicing is a fundamental process in gene expression and is the key to the pathology of numerous diseases, including cancer. Splicing deficits may affect the ability of cells to proliferate, and certain splicing isoforms have been found to act as drivers of cancer. Recently, potent antitumor natural products such as FR901464 have been discovered to trigger apoptosis in cells by inhibiting pre-mRNA splicing, thus affecting mRNA levels of oncogenes. Although potent, these natural anti-tumor agents are difficult to synthesize, hindering the potential of these molecules as ideal anticancer drug candidates.

Description

Researchers are exploring improved methodology for preparing and synthesizing these compounds and their analogs in easy ways. Additionally, certain synthetic analogs of these natural products have been demonstrated to possess a multi-fold increase in antitumor activity as compared to their natural parent molecule. Researchers at the University of Pittsburgh have synthesized novel analogs of the antitumor compound FR901464 that show much higher antitumor activity with an easier and more efficient means of synthesis. Three of these analogs are very stable and show antiproliferative activity against various cancer cell lines and multidrug-resistant cells in the picomolar range.

Applications

· Treating cancer

Advantages

· Increased antitumor activity compared to naturally occurring parent compound
· Easier to synthesize

Invention Readiness

In vivo data

IP Status

https://patents.google.com/patent/US7825267B2/en; https://patents.google.com/patent/US8309599B2/en; https://patents.google.com/patent/US9771377B2/en

Related Publication(s)

Albert, B. J., Sivaramakrishnan, A., Naka, T., Czaicki, N. L., & Koide, K. (2007). Total Syntheses, Fragmentation Studies, and Antitumor/Antiproliferative Activities of FR901464 and Its Low Picomolar Analogue. Journal of the American Chemical Society, 129(9), 2648–2659. https://doi.org/10.1021/ja067870m

Albert, B. J., McPherson, P. A., O’Brien, K., Czaicki, N. L., DeStefino, V., Osman, S., Li, M., Day, B. W., Grabowski, P. J., Moore, M. J., Vogt, A., & Koide, K. (2009). Meayamycin inhibits pre–messenger RNA splicing and exhibits picomolar activity against multidrug-resistant cells. Molecular Cancer Therapeutics, 8(8), 2308–2318. https://doi.org/10.1158/1535-7163.mct-09-0051

Osman, S., Albert, B. J., Wang, Y., Li, M., Czaicki, N. L., & Koide, K. (2010). Structural Requirements for the Antiproliferative Activity of Pre‐mRNA Splicing Inhibitor FR901464. Chemistry – A European Journal, 17(3), 895–904. https://doi.org/10.1002/chem.201002402

Osman, S., Waud, W. R., Gorman, G. S., Day, B. W., & Koide, K. (2011). Evaluation of FR901464 analogues in vitro and in vivo. Med. Chem. Commun., 2(1), 38–43. https://doi.org/10.1039/c0md00179a

Gao, Y., Vogt, A., Forsyth, C. J., & Koide, K. (2012). Comparison of Splicing Factor 3b Inhibitors in Human Cells. ChemBioChem, 14(1), 49–52. https://doi.org/10.1002/cbic.201200558

Gao, Y., & Koide, K. (2013). Chemical Perturbation of Mcl-1 Pre-mRNA Splicing to Induce Apoptosis in Cancer Cells. ACS Chemical Biology, 8(5), 895–900. https://doi.org/10.1021/cb300602j

Pham, D., & Koide, K. (2016). Discoveries, target identifications, and biological applications of natural products that inhibit splicing factor 3B subunit 1. Natural Product Reports, 33(5), 637–647. https://doi.org/10.1039/c5np00110b