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Alkaloid swainsonine is a human golgi α-mannosidase II (α-hGMII) inhibitor, which can modulate N-glycosylation and control cancer growth. However, its further clinical development has been suspended because of its unwanted inhibition against lysosomal mannosidase (α-hLM), causing the side effect of the accumulation of oligomannoses in the lysosome. 

The research team from Genomic Research Center was inspired by pyrrolidine-based alkaloid AN9 and bicyclic alkaloid swainsonine to design a hybrid skeleton to generate potential candidate scaffolds, followed by structural diversity called “Natural product-inspired combinatorial chemistry” (NPICC) to rapidly prepare this indolizidine-based molecular library (about 400 members). 

Through inhibition and selectivity study, the team discovered a compound named ACK900, which is not only an effective α-hGMII inhibitor but also a selective inhibitor. Further animal studies showed it is a promising anticancer agent. 

These research results are published in Chemical Science, the flagship journal of The Royal Society of Chemistry, and recommended by its Reviewers as one of the HOT Chemical Science articles published in 2022.