Pistorius, Dominik, Buntin, Kathrin, Weber, Eric, Richard, Etienne, Bouquet, Caroline, Wollbrett, Severine, Regenass, Hugo, Peon, Victor, Boehm, Marcel, Kessler, Regis, Gempeler, Thomas, Haberkorn, Anne, Wimmer, Laurin, Lanshoeft, Christian, Davis, John, Hainzl, Dominik, D'Alessio, Tony, Manchado Robles, Eusebio and Petersen, Frank (2021) Promoter-driven overexpression in Chromobacterium vaccinii facilitates access to FR900359 and yields novel low abundance analogs. Chemistry A European Journal.

Abstract

The access to the cyclic depsipeptide FR900359 (FR), a selective Gq protein inhibitor of high pharmacological interest and a potential lead molecule for targeted therapy of cancers with oncogenic Gαq/11 mutations, has been challenging ever since its initial discovery more than three decades ago. The recent discovery of Chromobacterium vaccinii as cultivable FR producer enables the development of approaches leading to a high-yielding, scalable and sustainable biotechnological process for production of FR, thereby removing this bottleneck. Here we characterize different promoters in exchange of the native promoter of the FR assembly line, resulting in a mutant with significantly increased production of FR. Thereby, the isolation and structure elucidation of novel FR analogs of low abundance was enabled. Further, we explored the antiproliferative activities of fifteen chromodepsins against uveal melanoma cell lines harboring Gαq/11 mutations and characterized the major metabolite of FR formed in plasma.

Item Type:	Article
Date Deposited:	23 Dec 2021 00:45
Last Modified:	23 Dec 2021 00:45
URI:	https://oak.novartis.com/id/eprint/45940