Structure-Based Design of a Novel Series of Potent, Selective Inhibitors of the Class I Phosphatidylinositol 3-Kinases

Abstract

A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.

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

“…Overall, besides the solvent exposed area, the PI3K active site contains three key regions (PI3Kγ, Figure 2) [30]: the hinge region (Val882), the affinity pocket (Lys833, Asp841, Tyr867, Ala885, Ser806, Tyr867) or the back pocket (DFG-motif, gate keeper and catalytic lysine) and the ribose pocket (Met804, Ala805, Lys802, Met953, Asp964, Trp812, etc.). Accordingly, the ATP-competitive PI3K inhibitors mainly include (1) The hinge linker binder: substituents containing hydrogen donor/acceptor to interact with Val882 ( morpholine, pyperazine, indole, quinolone, amine, methoxy group, etc.)…”

“…Although it's not an easy task, the discovery of isoform-specific PI3K inhibitors were facilitated by the elucidation of the X-ray crystal structure of PI3K isoforms and those of its complexes with diverse inhibitors [27, 29, 30]. Additionally, because mTOR is PI3K-related kinase that has similar ATP site with PI3K, a number of PI3K inhibitors could also exhibit inhibitory activity against mTOR (PI3K/mTOR dual inhibitors), which may be more effective by delivering a powerful two-spot inhibition of the pathway and have the advantage of being less susceptible to PI3K drug resistance and abrogating the compensatory effects of mTOR inhibitors [31].…”

“…In 2012, Smith et al [30] synthesized a series of highly selective class I PI3K inhibitors, starting from the potent PI3K/mTOR dual inhibitor 363 (PI3Kα Ki = 350 nM, mTOR IC 50 = 93 nM) with poor pharmacokinetic properties due to the glucuronidation of the phenolic substituents and extensive metabolism of the benzimidazole in vivo . As “pyridylpyrimidine and pyridylpurine scaffolds had been demonstrated to have good in vivo properties”, scaffold 364 was explored, with additional substituents to interact with the ribose pocket (Ki values <10 nM against PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ and>1000-fold selectivity against mTOR).…”

Triazine as a promising scaffold for its versatile biological behavior

“…Polarized, electron-withdrawing groups like cyano-analogue (104e) were also found to be 10-fold less optimal as compared to non-polarized electron-withdrawing groups like trifluoromethyl (104f) or trifluoromethoxy (104a). By combining 2-trifluoromethyl-or 2-trifluoromethoxy substituent M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 24 with a variety of 4-substituents like F (104g, IC 50 = 3 nM), OCH 3 (104h, IC 50 = 1 nM), Br (104i, IC 50 = 0.5 nM), resulted in no loss of enzyme activity (Fig. 44).…”

Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

“…One also wonders here if the Buchwald conditions which work better for heterocyclic substrates (although admittedly usually used for C-N bond formation) might not have also significantly improved yield for this C-C bond formation with reactants containing a host of heteroatoms. 35a,38 …”