Cancer cells are able to acquire resistance to therapies with a single target; therefore multitargeted therapies provide the best chance for success for effectively treating cancer. Some conventional anticancer drugs are multitargeted, but their ability to damage DNA in non-cancer cells reduces their therapeutic value. Versions of those same drugs that don’t damage DNA could revolutionize treatment of cancer, but as the DNA damaging factor is seen as an essential part of their functionality, they have not been extensively tested.

Finding a common target among multiple types of cancer has been historically difficult, but there are two known factors common to many types of tumor: p53 and nuclear factor kappa B (NF-κB). If p53 has been inactivated, or if NF-κB has been activated, cells become genomically instable, resistant to programmed cell death, and grow out of control. Finding drugs that target those two factors seems to be promising.

In the past, our research has found small molecules capable of simultaneously activating p53 and blocking NF-κB without damaging DNA, such as the antimalarial drug quinacrine. While quinacrine showed to be effective at fighting tumors in animal models, we wanted to find more potent molecules with similar properties. Our search led to isolating a group of compounds with similar effects on p53 and NF-κB and a lack of DNA damage, which we named curaxins. Curaxins functionally inactivate the FACT (facilitates chromatin transcription) complex, which results in the desired effects on p53 and NF-κB.

Curaxins were found by performing a structure-activity relationship study on libraries of models structurally similar to the quinacrine and CBLC000 molecules. The most effective results were CBLC000 (the original hit), CBLC100 (one of the most active compounds in vitro), and CBLC137 (selected for in vivo evaluation because it is highly stable metabolically and highly soluble in water). Curaxins are superiorly effective anti-cancer drugs because they are more toxic to tumor cells than normal cells and do not damage DNA, unlike the chemotherapy drug cisplatin. Tumor cells died after curaxin treatment in vitro, while normal cells stopped growing but resumed after ending curaxin treatment. As well, curaxins were comparable or superior in efficacy to the standard chemotherapeutic drugs 5-fluorouacil, irinotecan, and oxaliplatin, and a new targeted therapy, sunitinib.