Department of Chemistry and Biochemistry, University of Arkansas, USA
Ipomoeassin F is a flagship congener of a macrolide resin glycoside family with an embedded disaccharide core. In the NCI-60 cell line screen, ipomoeassin F showed the average GI50 of ~30 nM. The low correlation indices (< 0.5) from the COMPARE analyses with known anticancer agents suggest that ipomoeassin F has a novel mode of action. Built upon our early achievements in total synthesis and medicinal chemistry studies, we designed and synthesized a set of functional chemical probes of ipomoeassin F and subsequently performed systematic chemical proteomics studies. A long chain biotin affinity probe unambiguously revealed Sec61a (protein transport protein Sec61 subunit alpha isoform 1) as a primary binding partner of ipomoeassin F in live cells. Because Sec61a is the key component of the Sec61 translocon, the inhibitory effect of ipomoeassin F on the function of Sec61, that is, protein translocation and secretion, was further confirmed by various biological assays both in vitro and in vivo. The successful target identification of ipomoeassin F opens new avenues to exploring Sec61a as a potential therapeutic target for drug discovery.
Keywords: ipomoeassins, target identification, Sec61a, protein translocation and secretion.