HIF is a heterodimeric transcription factor composed of two subunits: HIF and HIF. HIF can be induced by hypoxia, growth Nintedanib factors, and oncogenes; whereas HIF protein is constitutively expressed in human cells.Various studies show that PIKAKT signaling is important for regulating HIF and VEGF expression. We have demonstrated that the expression of PIK dominant negative mutants or expression of PTEN inhibits tumor growth. Overexpression of PTEN mutants lacking phosphatase activity abrogates the inhibitory effect of PTEN on tumor growth, suggesting that the expression of PTEN requires its phosphotase activity to inhibit tumor growth in vivo.But the poor solubility and high toxicity of these inhibitors limit the clinical application.To overcome these shortcomings, derivatives of LY and wortmannin are being developed.It has been reported that PX, a wortmannin derivative has more potent and less toxic effects than wortmannin.It potentiates the antitumor activity of the EGFR inhibitor gefitinib against tumor xenografts induced by A nonsmall cell lung cancer in the early Entecavir hydrate stages of treatment. In addition, LY derivatives such as TGX and TGX, and PIK isoform selective inhibitors such as halenaquinone and deguelin, have been developed and shown to have greater water solubility, lower toxicity, improved pharmacodynamics, and more specific PIK selectivity. SF is a small molecule conjugate containing a panPIK inhibitor that inhibits all isoforms of PIK class IA and other key members of the PIK superfamily, including DNAPK.The perifosine treatment overcomes the cancer cell resistance to the treatment with chemotherapeutic drugs and radiation.VEGF and NFB have synergistic effects in inducing tumor angiogenesis.Akt is an essential downstream target of PIK for mediating the angiogenic signal.But their effects in vivo remain to be investigated.Triciribine is a known anticancer agent that was used in a number of clinical trials since the s. NCI cell lines with PIKCA mutation are more sensitive to triciribine treatment than those without the mutations. CCI, RAD, and AP are currently under the clinical trials for cancer treatment.Preclinical studies with these compounds indicate that these compounds have cytostatic activity as a single agent in animal models, and have synergistic effects for inhibiting tumor growth when they are used with conventional chemotherapy agent tamoxifen, or with radiation treatment.In clinical studies, these compounds have been shown to be effective against many types of solid cancers. RAD is administered orally for clinical application.RAD treatment enhances chemotherapy effect for treating relapsed nonsmall cell lung cancer and refractory gastrointestinal stromal tumor. AP is a phosphoruscontaining derivative of rapamycin, and developed in both intravenous and oral formulations for clinical trials.Akt is an essential downstream of PIK in regulating tumor growth and angiogenesis.The amplification and mutations of AKT are also observed in different cancers.Inhibition of signaling molecules in this pathway has been shown to have very strong effects on inhibiting tumor growth and angiogenesis in animal models.Akt activates downstream molecules mTOR and pSK for regulating tumor growth.In addition, PIK and mTOR inhibitors combined with other therapeutic drugs may have synergistic effects to inhibit tumor development.The future challenges are to develop highly specific inhibitors of these kinases, and to determine the clinical efficacy and maximum tolerated doses of these inhibitors for clinical cancer treatment.