Discovery and optimization of a series of 2-aminothiazole-oxazoles as potent phosphoinositide 3-kinase γ inhibitors

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents

“…Compound 298 was identified as an initial hit (PI3Kγ IC 50 = 5 nM) through HTS by Oka et al [97] and the docking mode indicated that nitrogen atoms in the acetylaminothiazole formed hydrogen bonds to the hinge Val882 ,while the benzoic acid moiety interacted with Lys807 and Lys833. Thus, they optimized the central heterocycles as the replacement of thiazole and identified oxazole derivative 299 (PI3Kγ IC 50 = 12 nM) as the lead for further optimization.…”

Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

“…78 The thiazole-oxazole core ( 252 & 254 ) was prepared by one of three routes and all three used bromoacetyl thiazole ( 250 ) as the starting material.…”

Identification and optimisation of a 4′,5-bisthiazole series of selective phosphatidylinositol-3 kinase alpha inhibitors

“…More recently a related 4 0 ,5-bisthiazole series of PI3Kc selective inhibitors has been reported originating from a high throughput screening hit. 10 Docking the 4 0 ,5-bisthiazole 8 into a homology model of PI3Ka, derived from a single-crystal X-ray structure of an aminothiazole based inhibitor bound into PI3Kc, 11 suggested that modifying the nature of the 2-substituent in the 4-linked thiazole moiety could further enhance the interaction within the affinity pocket. More specifically, the 2-isopropyl group was determined not to fully occupy the portion of the affinity pocket formed by the residues I800, I848, P778 and K802, and highlighted the possibility for larger groups to better fill this region, as depicted in Figure 4.…”