PI3K-alpha

May 2021

Phosphatidylinositol 3-kinase alpha (PI3Kα) is a lipid kinase that belongs to class IA of the PI3K kinase family together with beta and delta isoforms. Once activated, PI3Kα phosphorylates the phosphatidylinositol 4,5-bisphosphate (PIP2) lipid component on the cell membrane to phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 then activates downstream signaling components, such as AKT kinase that is involved in cell growth and survival. Dysregulation of the PI3Kα-mediated signaling pathway is strongly associated with cancerogenesis.

PI3Kα is a heterodimer composed of two subunits: catalytic p110α and regulatory p85α unit. The catalytic unit is encoded by the PIK3CA gene that is most frequently mutated in cancer. The hotspot mutations E542K and E545K occur in the helical domain of p110α and disrupt its interactions with the regulatory unit, which disables PI3Kα auto-inhibition. For this reason, PI3Kα is a critical anti-cancer drug target.

Alpelisib (Novartis) is the only FDA-approved drug that targets PI3Kα so far, classified as isoform-specific. However, this small molecule binds to the ATP-binding site that is almost identical among PI3K isoforms, and many off-target effects were observed. Scientists are currently interested in the discovery of allosteric drugs aiming to resensitize the active site and thus make it accessible once again to orthosteric drugs. This concept of dual therapy is very interesting and has been proven successful in other kinases.

3decision pocket explorer identifies pocket 66 as highly druggable (PDB ID: 4ovv).

The first step in the design of allosteric inhibitors is the identification of an allosteric binding site. In the case of PI3Kα, it remains unclear. 3decision can aid ones’ efforts to find potential allosteric sites thanks to the Pocket Explorer feature. Here users can explore all explicit and implicit pockets on the protein surface. Each pocket is characterized by properties such as druggability, polarity, volume, hydrophobicity, and charge. For example, pocket 66 (PDB ID: 4ovv), located at the bottom of the ABD domain, is predicted as highly druggable and with properties such as volume and charge similar to the orthosteric site (pocket 69). Pocket 66 could therefore be used as a starting point for a hit identification campaign.

Reference: Zhang M, Jang H, Nussinov R. PI3K inhibitors: review and new strategies. Chem Sci. 2020 May 19;11(23):5855-5865. doi: 10.1039/d0sc01676d. PMID: 32953006; PMCID: PMC7472334. https://pubmed.ncbi.nlm.nih.gov/32953006/

Have a look at this blog post where our team did a retrospective study on allosteric pocket detection in ABL1 using Pocket Explorer feature