Novel small molecule inhibitors of phosphatidylinositol-3,4,5-trisphosphate (PIP3)

Why is the target important?

The PI3 lipid kinase (PI3K) pathway is an important target for anti-cancer drug development because:

• It’s activated by growth factors, oncogenes (RAS), GPCRs, etc.
• It regulates an array of critical cellular functions, including survival, proliferation, metabolism and cell motility.
• PI3K and its downstream effectors are frequently over-activated in human cancer (in some types comparably to p53).
• Activity of PI3K contributes to survival, invasiveness and profound metabolic changes in cancer cells
• PIP3/PH domain binding is a critical non-redundant step in PI3K signaling, easily amenable to inhibition by a small molecule.
• Structural differences in binding pockets could be exploited to achieve selectivity

What data do we have?

Through a screening and drug development program, Dr. Alexei Degterev of Tufts University and his collaborators have identified a potent, non-phosphoinositide inhibitor of PIP3/protein binding termed YK-NCL-240 that displays significant anti-tumor activity in vitro and in vivo.

• Toxicity of YK-NCL-240 was tested in human ovarian (A2780), glioblastoma (U87MG), breast (T47D) and prostate (DU145) cancer cells. In these cancer types, YK-NCL-240 can effectively inhibit cell growth and induce cell death in vitro in both free and micellar formulations. Addition of TRAIL leads to synergistic induction of cell death.
• YK-NCL-240 can be incorporated into PEG-PE micelles in combination with TRAIL to get a synergistic effect between the two compounds. TRAIL-resistance is reversed in multiple TRAIL-resistant cancer cell lines.
• In a mouse xenograft study, YK-NCL-240 significantly inhibited A2780 tumor growth in a subcutaneous mouse model. Combination effect with TRAIL was also observed. Studies using higher dose of YK-NCL-240 are ongoing.
• YK-NCL-240 inhibits cellular migration in vitro, which may translate into the inhibition of angiogensis within tumors as well as inhibition of metastasis. The inhibition of migration by YK-NCL-240 has also been shown in T47D, U87MG and DU145 cells.
• YK-NCL-240 robustly suppresses the mTOR pathway downstream from Akt (in U87MG cells). Further characterization of the inhibition of Akt targets by YK-NCL-240 is ongoing.

Why is it competitive?

Previous efforts in developing PIP3 antagonists have focused on phosphoinositide-like molecules. However, as these molecules lack phosphate groups they require phosphorylation by endogenous kinases in the cells which creates a difficulty to achieve significant selectivity for PIP3 versus other phosphoinositides using this approach. Other issues, such as bioavalability and　metabolic stability may also limit utility of these molecules.