AI Article Synopsis
- PI3K is a key target in cancer treatment because its signaling pathway is often disrupted in many tumors.
- Researchers developed and tested a series of 4-amino-6-methyl-1,3,5-triazine sulfonamides as potential PI3K inhibitors.
- The most promising compound, compound 3j, demonstrated strong inhibition of PI3K, good selectivity for the target, and effective reduction of Akt phosphorylation in tumor models, along with good oral bioavailability in rats.
Article Abstract
Phosphoinositide 3-kinase (PI3K) is an important target in oncology due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of 4-amino-6-methyl-1,3,5-triazine sulfonamides were synthesized and evaluated as inhibitors of PI3K. The synthesis, in vitro biological activities, pharmacokinetic and in vivo pharmacodynamic profiling of these compounds are described. The most promising compound from this investigation (compound 3j) was found to be a pan class I PI3K inhibitor with a moderate (>10-fold) selectivity over the mammalian target of rapamycin (mTOR) in the enzyme assay. In a U87 MG cellular assay measuring phosphorylation of Akt, compound 3j displayed low double digit nanomolar IC(50) and exhibited good oral bioavailability in rats (F(oral)=63%). Compound 3j also showed a dose dependent reduction in the phosphorylation of Akt in a U87 tumor pharmacodynamic model with a plasma EC(50)=193 nM (91 ng/mL).
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| http://dx.doi.org/10.1016/j.bmcl.2012.06.078 | DOI Listing |
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