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Large J.M.,Cancer Research UK Research Institute | Torr J.E.,Cancer Research UK Research Institute | Raynaud F.I.,Cancer Research UK Research Institute | Clarke P.A.,Cancer Research UK Research Institute | And 8 more authors.
Bioorganic and Medicinal Chemistry | Year: 2011

Two classes of trisubstituted pyrimidines related to PI-103 1 have been prepared and their inhibitory activities against phosphatidylinositol 3-kinase (PI3K) p110α were determined. From those with direct 6-aryl substitution compound 11a was the most potent inhibitor with an IC50 value of 62 nM, and showed similar activity against other class 1a PI3K isoforms tested, p110β and p110γ. When a linking chain was introduced, as in the second exemplified class, compound 15f inhibited p110α with IC 50 142 nM, and showed greater selectivity towards p110α. Compounds of both classes showed promising inhibition of cellular proliferation in IGROV-1 ovarian cancer cells. Among compounds designed to replace the 3-phenolic motif with structural isosteres, analogues incorporating a 4-indazolyl group possessed enzyme and cellular activities comparable to the parent phenols. © 2010 Elsevier Ltd. All rights reserved. Source


Heffron T.P.,Genentech | Berry M.,Genentech | Castanedo G.,Genentech | Chang C.,Genentech | And 20 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor. © 2010 Elsevier Ltd. All rights reserved. Source


Sutherlin D.P.,Genentech | Sampath D.,Genentech | Berry M.,Genentech | Castanedo G.,Genentech | And 24 more authors.
Journal of Medicinal Chemistry | Year: 2010

The PI3K/AKT/mTOR pathway has been shown to play an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3Kγ-ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative to 1. The addition of a single methyl group to the optimized 5 resulted in 21, which had significantly reduced potency for mTOR. The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are highly selective, demonstrate knock down of pathway markers in vivo, and are efficacious in xenograft models where the PI3K pathway is deregulated. Both compounds were compared in a PI3KR mutated MCF7.1 xenograft model and were found to have equivalent efficacy when normalized for exposure. ©2010 American Chemical Society. Source


Heffron T.P.,Genentech | Wei B.,Genentech | Olivero A.,Genentech | Staben S.T.,Genentech | And 17 more authors.
Journal of Medicinal Chemistry | Year: 2011

Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3K has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3K vs PI3K selectivity for two chemical series. In the thienopyrimidine series of inhibitors, we propose that select ligands achieve selectivity derived from a hydrogen bonding interaction with Arg770 of PI3K that is not attained with the corresponding Lys777 of PI3K. In the benzoxepin series of inhibitors, the selectivity observed can be rationalized by the difference in electrostatic potential between the two isoforms in a given region rather than any specific interaction. © 2011 American Chemical Society. Source


Sutherlin D.P.,Genentech | Bao L.,Genentech | Berry M.,Genentech | Castanedo G.,Genentech | And 27 more authors.
Journal of Medicinal Chemistry | Year: 2011

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 1 for 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 4 that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC 50s of 5, 27, 7, and 14 nM for PI3Kα, β, δ, and γ, respectively, inhibits mTOR with a K i of 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, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer. © 2011 American Chemical Society. Source

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