Targeting PI3-Kinase Pathway: Patents Summary 2010 and 2011

Phosphatidylinositol-3-kinases, PI3Ks, constitute a lipid kinase family characterized by their ability to phosphorylate inositol ring 3´-OH group in inositol phospholipids generating the second messenger phosphatidylinositol-3,4,5-tris-phosphate (PIP3).

PI3K family is involved in a diverse set of cellular functions, including cell growth, proliferation, motility, differentiation, glucose transport, survival intracellular trafficking and membrane ruffling.

Activation of the PI3K pathway is a recurrent feature observed in human tumors, and the role of this pathway for the maintenance of the tumorigenic state has been clearly underlined.

PI3Ks can be categorized in three major class designed as class I, class II, or class III, depending on their subunit structure, regulation and substrate selectivity.

Class I:

Substrates for class I PI3Ks are phosphatidylinositol (PI), PI-4-phosphate (PI4P) and PI-4,5-biphosphate (PI(4,5)P2). Class I is divided into two groups (Ia and Ib) because of their activation mechanism and associated regulatory subunit. Class Ia PI3Ks includes PI3K p110a, p110b and p110d subtypes, and is typically activated by tyrosine kinase-coupled receptors. The class Ib is activated by a G-protein-coupled receptor via the subunit p110g.

Class II:

Contains PI3K C2a, b and g isoforms (characterized by the presence of C2 domains at C terminus). PI and PI4P are the known substrates.

Class III:

The substrate for this class is only the PI.

Scheme 1.PI3K Class Ia signaling pathway.

Activation of growth factor receptor tyrosine kinases results in phosphorylation on tyrosine residues of the receptor and leads to the recruitment of PI3Ks to the membrane (with or without adaptors). PI3Ks primarily phosphorylate phosphatidylinositol-4,5-bisphosphate (PIP2) on the plasma membrane to generate the second messenger, phosphatidylinositol-3,4,5-trisphosphate (PIP3). Accumulation of PIP3 on the cell membrane leads to the colocalization of signalling proteins, including Akt and PDK1.

Once activated, by phosphorylating several cellular proteins, Akt mediates the activation and the inhibition of several targets, resulting in cellular survival, growth and proliferation through various mechanisms.

The 3′-phosphatase PTEN dephosphorylates PIP3 and negatively regulates the PI3/Akt pathway.

Table 1. Current PI3K inhibitors in 2010 and 2011’s patents*

*Source WIPO