PI3K inhibitors: review and new strategies

Abstract

The search is on for effective specific inhibitors for PI3Kα mutants. PI3Kα, a critical lipid kinase, has two subunits, catalytic and inhibitory. PIK3CA, the gene that encodes the p110α catalytic subunit is a highly mutated protein in cancer. Dysregulation of PI3Kα signalling is commonly associated with tumorigenesis and drug resistance. Despite its vast importance, only recently the FDA approved the first drug (alpelisib by Novartis) for breast cancer. A second (GDC0077), classified as PI3Kα isoform-specific, is undergoing clinical trials. Not surprisingly, these ATP-competitive drugs commonly elicit severe concentration-dependent side effects. Here we briefly review PI3Kα mutations, focus on PI3K drug repertoire and propose new, to-date unexplored PI3Kα therapeutic strategies. These include (1) an allosteric and orthosteric inhibitor combination and (2) taking advantage of allosteric rescue mutations to guide drug discovery.

Fig. 1. PI3Kα conformation and oncogenic mutations. (A) PI3Kα sequence and the frequent oncogenic mutations in p110α (data obtained from TGCA database). (B) PI3Kα structures (PDB ID 4OVV) with the oncogenic mutations highlighted by the red surfaces. The close-up of (C) the PI3Kα conformation with nSH2 in the crystal structure (PDB ID ; 4OVV), (D) the conformation of PI3Kα with nSH2 released from the simulations, and (E) the conformation of the PI3Kβ with nSH2 released (PDB ID ; 2Y3A).

Fig. 2. Summary of the representative pan-PI3K and PI3K isoform-specific ATP-competitive inhibitors. The molecular structures are obtained from Drugbank.

Fig. 3. Structural insights into selectivity of alpelisib in PI3K isoforms. (A) The sequence alignment indicates the conserved and variable residues in PI3K for the interactions with alpelisib. (B) The structure of alpelisib interacting with the ATP pocket in PI3Kα (PDB ID 4JPS). (C) The structural comparison of the hinge regions in PI3K isoforms (PDB ID PI3Kβ-; 2Y3A; PI3Kγ-; 1E8X; PI3Kδ-; 4XEO). The alpelisib conformations in PI3K isoforms are modeled based on crystal structure of PI3Kα with alpelisib (PDB ID ; 4JPS).

Fig. 4. Summary of PI3Kα allosteric inhibitor pockets. (A) The full structure of PI3Kα with the allosteric pocket highlighted. The allosteric pocket for PIK-108 (PIK in the figure) is identified from the crystal structure of PI3Kα (PDB ID 4A55), the allosteric pockets F1–F5 are obtained from fragment-based screening and the allosteric pocket between ABD and kinase domain (AD in the figure) is proposed in the work. (B) The snapshot of PIK-108 interacting with a non-APT pocket in the C-lobe of kinase domain. The ATP is modeled based on the PI3K structure (PDB ID ; 1E8X). (C) The snapshot of the proposed allosteric pocket between ABD and N-lobe kinase domain.