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Of the four class I phosphoinositide 3-kinase (PI3K)isoforms,PI3Kα has justly received the most attention for its potentialin cancer therapy. Herein we report our successful approaches to achievePI3Kα vs PI3Kβ selectivity for two chemical series. Inthe thienopyrimidine series of inhibitors, we propose that selectligands achieve selectivity derived from a hydrogen bonding interactionwith Arg770 of PI3Kα that is not attained with the correspondingLys777 of PI3Kβ. In the benzoxepin series of inhibitors, theselectivity observed can be rationalized by the difference in electrostaticpotential between the two isoforms in a given region rather than anyspecific interaction. [ABSTRACT FROM AUTHOR]

The discovery of 2(GDC-0980), a class I PI3K and mTOR kinase inhibitor for oncology indications, is described. mTOR inhibition was added to the class I PI3K inhibitor 1(GDC-0941) scaffold primarily through the substitution of the indazole in 1for a 2-aminopyrimidine. This substitution also increased the microsomal stability and the free fraction of compounds as evidenced through a pairwise comparison of molecules that were otherwise identical. Highlighted in detail are analogues of an advanced compound 4that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC50s of 5, 27, 7, and 14 nM for PI3Kα, β, δ, and γ, respectively, inhibits mTOR with a Kiof 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer. [ABSTRACT FROM AUTHOR]

The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report the optimization of the dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibition, which led to the discovery of compound 24(PF-00868554). Compound 24is a potent and selective HCV polymerase inhibitor with a favorable pharmacokinetic profile and has recently entered a phase II clinical evaluation in patients with genotype 1 HCV. [ABSTRACT FROM AUTHOR]

The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure−activity relationship (SAR) studies led to the identification of compounds, exemplified by 23and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles. [ABSTRACT FROM AUTHOR]