RAS is the name of a series of related proteins commonly expressed in all cell lineages and organs. Specifically, RAS is a prototype member of the Ras protein superfamily. All proteins are related to 3D structure and regulate a variety of cell behaviors. Besides, mutations in the ras gene family occur in about 95% of Pancreatic Cancers (PCs). Moreover, carcinogenic KRAS are essential for PC startup and maintenance.

The activation of the NF-κB signaling pathway is closely related to the development of OA and other factors downstream of HIF-2α. Furthermore, sustained NF-κB activation stimulates regulatory transcription factors such as HIF-2α and Runx2. These factors can increase the production of integrins and metalloproteinases with prp5 and MMP-13. Meanwhile, this promotes chondrocytes from hypertrophic state to terminal hypertrophic state. Here, we will introduce an orally active tricarbonylmethane agent, CMC2.24.

CMC2.24 is an orally active tricarbonylmethane agent.

First of all, CMC2.24 is effective against pancreatic tumor in mice by inhibiting Ras activation and its downstream effector ERK1/2 pathway. Nonetheless, CMC2.24 is also a potent inhibitor of zinc-dependent MMPs with IC₅₀s ranging from 2.0-69 μM. Importantly, CMC2.24 alleviates osteoarthritis progression by restoring cartilage homeostasis and inhibiting chondrocyte apoptosis via the NF-κB/HIF-2α axis.

In the second place, CMC2.24 with 0-60 μM for 24 hours inhibits pancreatic cancer growth in a concentration-dependent manner. Interestingly, CMC2.24 reduces STAT3^Ser727 phosphorylation levels. CMC2.24 induces mitochondrial reactive oxygen species and mitochondrial cell death in pancreatic cancer cells. Particularly, CMC2.24 induces mitochondrial reactive oxygen species and intrinsic apoptosis.

Last but not the least, CMC2.24 with 50 mg/kg by p.o. for five times per week during 17 days, inhibits the growth of pancreatic cancer xenografts. Obviously, CMC2.24 inhibits the growth of human PC through a strong cytokinetic effect. Additionally, CMC2.24 inhibits ERK signaling pathway in PC cells and xenografts.

All in all, CMC2.24 is an orally active tricarbonylmethane agent.

References:

Mallangada NA, et al. Mol Carcinog. 2018;57(9):1130-1143.