Tivatinib (ARQ-197)

[donocco]

Elizabeth

Since you are interested in this Ill show you how complicated it gets. Affinitor is an anticancer drug that inhibits M-Tor. There are two froms of M-Tor and Affinitor mostly inhibits M-Tor1. When you inhibit Mtor1 you inhibit what are called S6 Kinases. This is good in treating cancer because, in simple language, S6 Kinases stimulate cancer cell growth.

But inhibiting S6 kinases by inhibiting M-Tor also causes a problem. When S6 Kinase is inhibited, a protein called AKT becomes more active and AKT activates M-Tor. So by inhibiting S6 Kinases by inhibiting M-Tor you eventually re-stimulate M-Tor all over again by activating AKT. You can see why this material makes your head spin.

I started talking about C-Met or Hepatocyte Growth Factor Receptor. Activating C-Met activates a protein called GAB1 and GAB1 activates a protein called P13K and P13K activates AKT and AKT activates M-tor1 and M-Tor1 activates S6 Kinase and S6 Kinase stimulates cancer growth. By blocking Mtor1 you block S6 Kinase and as far as cancer treatment goes, that is a good thing. But blocking S6 Kinase overactivates AKT and you end up with more than normal M-Tor1 action. Its like a loop that goes round and round.

Since P13K stimulates AKT, maybe by combining an M-Tor inhibitor like Affinitor with a P13K inhibitor like BMK-120 (known as Buparlisib, an investigational drug), you can get the positive anticancer activity of an M-Tor inhibitor without restimulating more M-Tor activity in the cell. You can see how complicated this is.

Paul

PS P13K acivity is important in insulin action in normal cells. This must be why the P13K inhibitors like BMK-120
have high blood sugar (hyperglycemia) as a common side effect.