Overexpression and activation of the murine double minute 2 (MDM2) or nuclear factor of activated T cells 1 (NFAT1) oncoproteins occur frequently in pancreatic cancer. Many MDM2 inhibitors target MDM2-p53 binding and have little or no effect on cancers without functional p53, such as pancreatic cancer.

Besides, nuclear factor of activated T cells 1 (NFAT1) promotes cancer cell proliferation, enhances cell-cycle progression, suppresses apoptosis, induces migration and invasion. And these effects leads to drug resistance through both calcineurin-dependent and -independent pathways.

Therefore, a study from Wei Wang discovered and identified a dual inhibitor of MDM2 and NFAT1, MA242. In the study, the authors aimed to demonstrate the therapeutic efficacy and safety of MA242 alone and in combination with gemcitabine. They aimed to confirm its mechanisms of action in pancreatic cancer, especially in those deficient in functional p53.

As a result,  MA242 is a potent and selective dual inhibitor of MDM2 and NFAT1, independent of p53. In vitro, MA242 selectively induced pancreatic cancer cell death and inhibits MDM2 and NFAT1 expression, independent of p53. MA242 treatment with the concentration of 0.1 μM induced a significant reduction of the MDM2 and NFAT1 expression in Panc-1 cell. Additionally, MA242 significantly inhibited pancreatic cancer cell growth, with IC50 values ranging from 0.1 to 0.4 μM.

Consistent with the in vitro results, in animals, MA242 downregulated the expression of MDM2 and NFAT1. It also upregulated the expression levels of p21 and cleaved-PARP in both AsPC-1 and Panc-1 orthotopic tumors. Furthermore, MA242 sensitizes pancreatic cancer cells to gemcitabine treatment in vitro and in vivo.

Thus, MA242 is a promising clinical candidate to treat pancreatic cancer.

Wang W, et al. Discovery and Characterization of Dual Inhibitors of MDM2 and NFAT1 for Pancreatic Cancer Therapy. Cancer Res. 2018 Oct 1;78(19):5656-5667.