Inavolisib

Inavolisib is a mutant-selective PI3Kα inhibitor that targets the p110α catalytic subunit of PI3Kα, specifically in its mutated form. PI3Kα is a critical component of the PI3K pathway, which is activated by receptor tyrosine kinases (RTKs) at the plasma membrane. This pathway regulates cell growth, survival, and metabolism. In non-mutant settings, inhibition of PI3Kα by standard PI3K inhibitors leads to initial suppression of the pathway. However, feedback mechanisms often upregulate RTK expression, leading to sustained PI3K signaling despite the inhibition.

In contrast, inavolisib selectively binds to the mutant p110α/p85β complex, triggering proteasome-mediated degradation of the mutant p110α subunit. This degradation disrupts downstream signaling and prevents feedback reactivation of the PI3K pathway. By degrading mutant p110α, inavolisib achieves sustained inhibition of PI3K signaling, particularly in tumors driven by activating mutations in PI3Kα.