The utility of natural products for identifying anticancer agents has been highly
pursued in the last decades and over 100 drug molecules in clinic are natural products or natural
product-derived compounds. Natural products are believed to be able to cover unexplored
chemical space that is normally not occupied by commercially available molecule libraries.
However, the low abundance and synthetic intractability of natural products have limited their
applications in drug discovery. Recently, the identification of biologically relevant fragments
derived from biologically validated natural products has been recognized as a powerful strategy
in searching new biological probes and drugs. The spirocyclic oxindoles, as privileged structural
scaffolds, have shown their potential in designing new drugs. Several anticancer drug
candidates such as SAR405838, RO8994, CFI-400945 and their bioisosteres are undergoing
clinical trials or preclinical studies. To highlight the significant progress, we focus on
illustrating the discovery of SAR405838, RO8994, CFI-400945 and their bioisosteres for cancer therapy using
substructure-based strategies and discussing modes of action, binding models and preclinical data.