xenografted model [64, 65]. Moreover SAR405 synergized with mTOR inhibitor
everolimus for cell proliferation inhibition in renal carcinoma models [66].
5 PI3Kβ Inhibitor: Leveraging Water Molecules
in the Active Site for Selectivity Enhancement
The class I PI3K lipid kinases are key mediators of the Akt pathway which they
contribute to activate by phosphorylating the phosphatidylinositol-4,5-bisphosphate
(PIP2) on the 3-position to form phosphatidylinositol-3,4,5-trisphosphate (PIP3)
[67]. The class I PI3Ks comprises four isoforms PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ
which share high level of sequence identity. Whereas PI3Kα, PI3Kβ, and PI3Kδ
(subclass IA members) can be activated by receptor tyrosine kinases or GPCRs,
PI3Kγ the single member of the subclass IB is activated by GPCRs. In addition, class
IA PI3Ks are heterodimer enzymes composed of a p85 regulatory subunit and a p110
catalytic subunit harboring the kinase domain [68]. PIP3 then recruits PDK1 and Akt
(PKB) at the membrane surface which allows phosphate transfer from PDK1 to Akt
(on Thr308). Additional phosphorylation of Akt on Ser473 by mTORC2 results in
full activation of Akt triggering downstream upregulation of effectors and elicits
cellular processes as proliferation, angiogenesis, survival, and metabolism [69]. In
normal cells, the Akt pathway is tightly regulated by the phosphatase and TENsin
homologue (PTEN) which dephosphorylates PIP3 back into PIP2. In cancer cells,
several activating genetic abnormalities have been detected in the Akt pathway such
as gain of function mutations in PIK3CA gene, which encodes for the p110α
catalytic subunit of PI3Kα, amplification of the PIK3CA gene, and deletion of the
Fig. 13 (a) X-ray structure of compound 16 (displayed with carbon atoms in orange) bound to
VPS34; surface of VPS34 ATP-binding pocket is displayed in grey. (b) Superimposition of
co-crystal complex of compound 16 (carbon atoms colored in orange) bound to VPS34 and of
X-ray structure of PI3Kδ (PDB code 2WXL; protein carbon atoms and surface colored in green).
VPS34 protein is not displayed. Steric clashes between compound 16 and residues Ile825 and
Met900 of PI3Kδ are depicted as red dotted lines
Achieving High Levels of Selectivity for Kinase Inhibitors
111
everolimus for cell proliferation inhibition in renal carcinoma models [66].
5 PI3Kβ Inhibitor: Leveraging Water Molecules
in the Active Site for Selectivity Enhancement
The class I PI3K lipid kinases are key mediators of the Akt pathway which they
contribute to activate by phosphorylating the phosphatidylinositol-4,5-bisphosphate
(PIP2) on the 3-position to form phosphatidylinositol-3,4,5-trisphosphate (PIP3)
[67]. The class I PI3Ks comprises four isoforms PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ
which share high level of sequence identity. Whereas PI3Kα, PI3Kβ, and PI3Kδ
(subclass IA members) can be activated by receptor tyrosine kinases or GPCRs,
PI3Kγ the single member of the subclass IB is activated by GPCRs. In addition, class
IA PI3Ks are heterodimer enzymes composed of a p85 regulatory subunit and a p110
catalytic subunit harboring the kinase domain [68]. PIP3 then recruits PDK1 and Akt
(PKB) at the membrane surface which allows phosphate transfer from PDK1 to Akt
(on Thr308). Additional phosphorylation of Akt on Ser473 by mTORC2 results in
full activation of Akt triggering downstream upregulation of effectors and elicits
cellular processes as proliferation, angiogenesis, survival, and metabolism [69]. In
normal cells, the Akt pathway is tightly regulated by the phosphatase and TENsin
homologue (PTEN) which dephosphorylates PIP3 back into PIP2. In cancer cells,
several activating genetic abnormalities have been detected in the Akt pathway such
as gain of function mutations in PIK3CA gene, which encodes for the p110α
catalytic subunit of PI3Kα, amplification of the PIK3CA gene, and deletion of the
Fig. 13 (a) X-ray structure of compound 16 (displayed with carbon atoms in orange) bound to
VPS34; surface of VPS34 ATP-binding pocket is displayed in grey. (b) Superimposition of
co-crystal complex of compound 16 (carbon atoms colored in orange) bound to VPS34 and of
X-ray structure of PI3Kδ (PDB code 2WXL; protein carbon atoms and surface colored in green).
VPS34 protein is not displayed. Steric clashes between compound 16 and residues Ile825 and
Met900 of PI3Kδ are depicted as red dotted lines
Achieving High Levels of Selectivity for Kinase Inhibitors
111