Dimers of isatin derived -methylene--butyrolactone as potent anti-cancer agents.
Additional Document Info
The IKK-NFB complex is a key signaling node that facilitates activation of gene expression in response to extracellular signals. The kinase IKK and the transcription factor RELA have been targeted by covalent modifiers that bind to surface exposed cysteine residues. A common feature in well characterized covalent modifiers of RELA and IKK is the Michael acceptor containing -methylene--butyrolactone functionality. Through synthesis and evaluation of a focused set of -methylene--butyrolactone containing spirocyclic dimers (SpiDs) we identified SpiD3 as an anticancer agent with low nanomolar potency. Using cell-free and cell-based studies we show that SpiD3 is a covalent modifier that generates stable RELA containing high molecular weight complexes. SpiD3 inhibits TNF-induced IB phosphorylation resulting in the blockade of RELA nuclear translocation. SpiD3 induces apoptosis, inhibits colony formation and migration of cancer cells. The NCI-60 cell line screen revealed that SpiD3 potently inhibits growth of leukemia cell lines, making it a suitable pre-therapeutic lead for hematological malignancies.