A phosphoinositide 3-kinase inhibitor


A phosphoinositide 3-kinase inhibitor (PI3K) is a class of medical drug that functions by inhibiting one or more of the phosphoinositide 3-kinase enzymes, which are part of the PI3K/AKT/mTOR pathway, an important signaling pathway for many cellular functions such as growth control, metabolism and translation initiation. Within this pathway there are many components, the inhibition of which may result in tumor suppression.
1.1 ATP-competitive mTORC1/mTORC2 inhibitors
mTOR inhibitors can inhibit all phosphorylation events catalyzed by mTORC1 and also affect mTORC2. In preclinical studies, ATP-competitive mTORC1/mTORC2 inhibitors displayed more dominant anti-proliferative and pro-apoptotic things, and more complete embarrassment of mTORC1 outputs than rapalogs 3. Various of these drugs like Sapanisertib, have been investigated in clinical trials for a wide range of malignancies.
The inhibition of mTOR offers many opportunities for cancer treatment. However, development of safe and effective treatments is challenging because of the importance of mTOR signaling for normal cell tasks. Current studies point in new directions, like blocking relevant actions downstream of mTORC1, and could offer new experimental openings.
Dactolisib is an imidazoquinoline derivative acting as an inhibitor of mTOR/PI3K. 4 It is being investigated as a possible cancer treatment. Dactolisib is an orally bioavailable imidazoquinoline directing the phosphatidylinositol 3 kinase (PI3K) and the mammalian target of rapamycin (mTOR), with potential antineoplastic activity. Dactolisib inhibits PI3K kinase and mTOR kinase in the PI3K/AKT/mTOR kinase signaling pathway, which may effect in tumor cell apoptosis and growth inhibition in PI3K/mTOR-overexpressing tumor cells. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy. mTOR is a serine/threonine kinase downstream of PI3K, may also be triggered of PI3K. To overcome such clinical concerns, we are studying the application potential of the new and highly specific PI3K/mTOR inhibitor, dactolisib, in GBM 5, 6. Dactolisib, an orally directed potent dual inhibitor of PI3K/mTOR, indicates promising anti-solid tumor efficacy.
Sapanisertib is an investigational, orally available, potent and highly selective mTORC1/2 inhibitor demonstrating promise in numerous malignancies. This phase I study (NCT02412722) evaluated the safety, tolerability, pharmacokinetics and antitumor activity of single-agent TAK-228 (milled capsules), administered daily (QD) or weekly (QW) and in mixture with paclitaxel in patients with advanced solid tumors. 7
From the detailed study of Dactolisib and Sapanisertib we have design novel 4-Amino-3-(isoquinolin-4-yl)-1H-pyrazolo 3,4-dpyrimidin derivatives as Dual PI3K/ mTOR inhibitors with the help of in sillico analysis and molecular docking studies. In Fig. 1 the d

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