PI-103 Hydrochloride is a potent dual inhibitor of PI3K and mTOR, demonstrating inhibitory IC50 values of 8 nM for p110α, 88 nM for p110β, 48 nM for p110δ, 150 nM for p110γ, 20 nM for mTORC1, and 83 nM for mTORC2, respectively. Additionally, it inhibits DNA-PK with an IC50 of 2 nM and induces autophagy [1] [2] [3] [4].

PI-103 shows antiproliferative properties in a panel of human cancer cell lines [1]. PI-103 is essentially cytostatic for cell lines and induced cell cycle arrest in the G1 phase. In blast cells, PI-103 inhibits leukemic proliferation, the clonogenicity of leukemic progenitors and induces mitochondrial apoptosis, especially in the compartment containing leukemic stem cells [2]. PI-103 potently inhibits both the rapamycin-sensitive (mTORC1, IC 50 =20 nM) and rapamycin-insensitive (mTORC2, IC 50 =83 nM) complexes of the protein kinase mTOR [4].

PI-103 shows therapeutic activity against a range of human tumor xenografts, exhibiting inhibition of angiogenesis, invasion, metastasis, and direct antiproliferative effects [1]. PI-103 induces immunosuppression promoting in vivo tumor growth and inhibiting apoptosis. Tumors from PI-103-treated mice shows higher levels of cyclin D1 and more proliferating cells [3].