New PI3K Inhibitor Receives US FDA Approval

Before discussing the most recently approved PI3K inhibitor let's review what exactly are the PI3K enzymes and what do they do.

The phosphatidylinositol-3-kinases, PI3K (also designated PIP3K) represent a family of both receptor-activated and non-receptor-activated phosphatidylinositol phosphate kinases (PIPK). Phosphatidylinositol-4,5-bisphosphate (PIP₂; also designated PtdIns-4,5-P₂) is a primary substrate for the PI3K family enzymes that phosphorylate the membrane lipid on the 3-OH on inositol to generate phosphatidylinositol-3,4,5-trisphosphate, PIP₃ (also designated PtdIns-3,4,5-P₃).

Initial characterization of PI3K activity found that it was associated with two protein subunits, one of 85 kDa (p85) and the other of 110 kDa (p110). Further work demonstrated that the p85 subunit had no intrinsic PI3K activity but that it contained a protein-protein interaction domain of the SRC homology domain 3 (SH3) type and two phosphotyrosine-binding sites of the SRC homology domain 2 (SH2) type. The presence of the SH3 domain allows p85 and p110 to form a heterodimer and the presence of the SH2 domains allows the heterodimer to bind to phosphorylated tyrosine docking sites on growth factor receptors harboring intrinsic tyrosine kinase activity such as the epidermal growth factor receptor (EGFR).

Numerous studies identified several different p110 and p85 subunit genes resulting in the characterization of PI3K enzymes as a large family of enzymes. The receptor-activated PI3K members include both receptor tyrosine kinase (RTK) and G-protein coupled receptor (GPCR) activated isoforms. The GPCR activated PI3K enzymes consist of the p110 catalytic subunit and a different regulatory subunit identified as p101. The p101 subunit facilitates interaction of the catalytic p110 subunit with the βγ-subunits that are released from the heterotrimeric G-proteins activated by GPCR stimulation.

Another class of PI3K enzymes were characterized that function as monomeric enzymes. These PI3K harbor a C-terminal C2 domain (a membrane targeting domain that binds Ca²⁺ ions) and are, therefore, referred to as PI3K-C2 kinases. The result of this large body of work was the classification of PI3K enzymes into three distinct groups based upon structural and biochemical characteristics. The three groups are designated class I, class II, and class III.

Class I PI3K enzymes are receptor-regulated PIP₂ kinases. Mammals express two subgroups of the class I PI3K isoforms, with the IA subgroup representing the RTK-activated enzymes and the IB subgroup representing the GPCR-activated enzymes. Within the class IA subgroup there are four catalytic subunit encoding genes and two regulatory subunit encoding genes. The catalytic subunits of class IA PI3K enzymes are designated p110α (PIK3CA gene), p110β (PIK3CB gene), p110δ (PIK3CD gene), and p110γ (PIK3CG). The two class IA regulatory subunits are designated p85α (PIK3R1 gene) and p85β (PIK3R2 gene). The class IB PI3K enzyme is a heterodimer composed of only one catalytic subunit (the p110γ protein) and one of two regulatory subunits. The two regulatory subunits are the original p101 subunit (encoded by the PIK3R5 gene) and the protein encoded by the PIK3R6 gene (originally identified as p87PIKAP).

Class II PI3K enzymes are the PI3K-C2 kinases. Humans express three class II PI3K isoforms identified as PI3K-C2α, PI3K-C2β, and PI3KJ-C2γ. The PI3K-C2α enzyme is encoded by the PIK3C2A gene, the PI3K-C2β enzyme is encoded by the PIK3C2B gene, and the PI3K-C2γ enzyme is encoded by the PIK3C2G gene.

The class III PI3K enzyme (there is only a single class III enzyme) is the phosphatidylinositol-specific enzyme (human homolog of yeast Vps34) which is encoded by the PIK3C3 gene. The human PIK3C3 protein forms a heterodimer with a regulatory subunit that is designated p150 (Vps15 in yeast) which is encoded by the PIK3R4 gene.

The enzymes of the PI3K family harbor domains, distinct from the catalytic domain, that are critical to their function. These domains are also found in numerous other signal transduction proteins. One important domain in PI3K enzymes is the pleckstrin homology (PH) domain, a loosely conserved modular domain of about 120 amino acids. The PH domain is found in all the class I PI3K enzymes. The significance of the PH domain is that it binds to PIP₂ as well as to PIP₃ and to phosphatidylinositol-3,4-bisphosphate.

Several PI3K inhibitors have already been approved for use in various disease state:

PI3K inhibitors are finally coming of age

The most recent approval for a PI3K inhibitor is identified as leniolisib (drug name Joenja).

FDA approves PI3K inhibitor for a rare immune disorder

Leniolisib is an orally administered small organic molecule that inhibits the particular PI3K identified as PI3Kδ (PI3Kdelta). This drug is aimed at treating the rare immune system disorder known as APDS (activated PI3Kδ syndrome). Mutations in the gene that encodes PI3Kδ (PIK3CD) that result in aberrant activation of the enzyme (referred to as gain-of-function mutations) are the cause of APDS. APDS is associated with an increased risk of respiratory infection and airway damage due to the activated PI3Kδ causing a disruption in immune cell development leading to lymphoproliferation, cytopenia, and other complications.

The study, whose results led to the FDA approval,  found the drug shrunk lymph node size and raised naïve B cell counts which strongly suggested that the drug helped reverse the underlying immune defect.