MM-129 as a Novel Inhibitor Targeting PI3K/AKT/mTOR and PD-L1 in Colorectal Cancer

SIMPLE SUMMARY: MM-129 (1,2,4-triazine derivative) is a novel promising drug candidate against colon cancer. It has the ability to inhibit intracellular pathways promoting tumorigenesis with a simultaneous reduction of PD-L1 expression, a key element of the cancer immune escape axis. MM-129 may also act as a chemosensitizer, overcoming chemoresistance against 5-FU, the first-line agent in the chemother-apy of colon cancer. Our results significantly expand knowledge and help better understand the process of tumorigenesis, the intracellular pathways involved, and the mutual interactions of in-dividual proteins, and create the possibility of their pharmacological blockade. There is a real chance that the obtained results and the conclusions drawn on their basis will help in the development of a new, effective therapy, which could be an attractive alternative to the already existing methods of colon cancer treatment. ABSTRACT: Background and aims: The purpose of the present study was to examine the pharmacodynamics features of MM-129 (1,2,4-triazine derivative) as a novel promising drug candidate against colon cancer. Methods: MM-129 was assessed for antitumor activity through an in vivo study on Cby.Cg-Foxn1nu/cmdb mice. The mechanistic studies investigated cellular affinity of a new 1,2,4-triazine derivative by measuring levels of intracellular/extracellular signal molecules participating in tumorigenesis. Results: The results revealed that MM-129 significantly reduced tumor growth in mice challenged with DLD-1 and HT-29 cells. It exerted the ability to inhibit intracellular molecules promoting tumorigenesis and inducing cell cycle arrest, like Akt, mTOR, and CDK2. Simultaneously, it was able to downregulate PD-L1 expression, which involves immunological self-tolerance. Combined administration of MM-129 and 5-fluorouracil (5-FU) additionally amplified these effects, which were manifest as an increase population of cells in the G0/G1 phase. Conclusions: A novel 1,2,4-triazine derivative with a dual mechanism of antitumor activity—MM-129, may act as a chemosensitizer, overcoming chemoresistance against 5-FU, the first-line agent in the chemotherapy of colon cancer.