PI3K-AKT-mTOR pathway inhibitors

Our company offers a comprehensive approach to design drugs targeting an entire pathway instead of only one target. The combination of assay systems provides us the possibility to target each member of the signal transduction pathway, in order to develop complex therapies.

Biological significance

Lately, PI3K-AKT-mTOR signal transduction cascade became an attractive target for pathway targeted drug design. The ATP-competitive compounds targeting mTOR, inhibit mTORC2, mTORC1 and in most cases PI3K as well, due to their kinase domains’ high structural similarity. This implies that ATP-competitive mTOR can target the pathyway on different points. Besides, AKT proteins are kinases of great interest also, involved in this pathway. Combination of AKT and mTOR/PI3K inhibitors may lead to apoptosis, without the counter effect of mTOR inhibition solely, that leads to overdrive AKT activity by a feedback mechanism.

Results

Although this project and the entire approach are quite new, we have already developed more than forty ATP-competitive mTOR inhibitors. The first hits of this family came from our Nested Chemical Library™. We synthesized forty-five derivatives on the basis of these hits. Among these derivatives we have found two nanomolar molecules (VCC-668662:01 IC50 = 51 nM and VCC-405567:02 IC50 = 748 nM). In parallel with the synthetic work, we developed and validated a comparative AKT1 and AKT2 assay system and started to develop an S6K kinase assay.