Advancements in Cancer Therapy: Synergistic Dual and Triple Inhibitors Targeting PIM and PI3K/mTOR Pathways

The PI3K/AKT pathway is frequently activated in cancer, and while inhibitors of this pathway have been developed, their effectiveness is often hindered by the activation of compensatory signaling pathways. PIM kinases represent one such compensatory pathway that can promote resistance to therapies targeting AKT and mTOR. This has led to the exploration of dual and triple inhibitors that target both PIM kinases and components of the PI3K/AKT/mTOR pathway.

A new series of compounds, ETP-539/(IBL-202) and ETP-339/(IBL-301), have been identified that exhibit dual PIM/PI3K and triple PIM/PI3K/mTOR inhibitory activity, respectively. These compounds have demonstrated low nanomolar inhibition of their target kinases and high selectivity against a panel of 456 kinases. Both inhibitors have shown increased potency over selective inhibitors in various cancer cell lines, including leukemia, lymphoma, colon, and NSCLC.

Mechanistic studies have indicated that these inhibitors induce cell cycle arrest and apoptosis in AML and NSCLC cell lines and decrease the expression of biomarkers. The inhibitors have been optimized for in vitro ADME properties and have shown excellent oral bioavailability. In vivo testing in mouse models of AML and NSCLC has demonstrated significant antitumor efficacy and downregulation of targeted biomarkers without any observed toxicity.

The findings provide a strong basis for the continued preclinical development of ETP-539/(IBL-202) and ETP-339/(IBL-301) and suggest their potential clinical utility in treating AML and NSCLC tumors.