Phosphoinositide 3-kinases (PI3K) are important targets in the continuing search for effective cancer therapeutics. A detailed understanding of the molecular basis of inhibitor selectivity between the four highly homologous isoforms (PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ) will aid the rational design of isoform selective inhibitors, in turn providing vital information towards the optimal selectivity profile for clinical success. Our aim is to probe the effect of substitutions around a 2-morpholinyl-1,3,5-triazine scaffold on both potency and selectivity, seeking to understand the molecular basis for observed selectivity using a combination of in silico modeling and site-directed mutagenesis.

The synthesis of a series of 2-morpholinyl-1,3,5-triazine derivatives probing interactions with one of the non-conserved residues in PI3Kα, Q859 (aspartate, lysine and asparagine in PI3Kβ, γ and δ, respectively) has been undertaken. Many of these substitutions have proven successful in increasing selectivity for the alpha isoform. Testing of inhibitors against isoform mutants, coupled with docking into available crystal structures, confirm the role of Q859 in conferring selectivity.

These results suggest that Q859 may be an important residue to target in the rational design of PI3Kα inhibitors that will further aid in elucidating the therapeutic effectiveness of PI3Kα isoform selective inhibitors.