Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941

Abstract

The phosphatidylinositide 3-kinase pathway is frequently deregulated in human cancers and inhibitors offer considerable therapeutic potential. We previously described the promising tricyclic pyridofuropyrimidine lead and chemical tool compound PI-103. We now report the properties of the pharmaceutically optimized bicyclic thienopyrimidine derivatives PI-540 and PI-620 and the resulting clinical development candidate GDC-0941. All four compounds inhibited phosphatidylinositide 3-kinase p110α with IC 50 ≤ 10 nmol/L. Despite some differences in isoform selectivity, these agents exhibited similar in vitro antiproliferative properties to PI-103 in a panel of human cancer cell lines, with submicromolar potency in PTEN-negative U87MG human glioblastoma cells and comparable phosphatidylinositide 3-kinase pathway modulation. PI-540 and PI-620 exhibited improvements in solubility and metabolism with high tissue distribution in mice. Both compounds gave improved antitumor efficacy over PI-103, following i.p. dosing in U87MG glioblastoma tumor xenografts in athymic mice, with treated/control values of 34% (66% inhibition) and 27% (73% inhibition) for PI-540 (50 mg/ kg b.i.d.) and PI-620 (25 mg/kg b.i.d.), respectively. GDC-0941 showed comparable in vitro antitumor activity to PI-103, PI-540, and PI-620 and exhibited 78% oral bioavailability in mice, with tumor exposure above 50% antiproliferative concentrations for >8 hours following 150 mg/kg p.o. and sustained phosphatidylinositide 3-kinase pathway inhibition. These properties led to excellent dose-dependent oral antitumor activity, with daily p.o. dosing at 150 mg/kg achieving 98% and 80% growth inhibition of U87MG glioblastoma and IGROV-1 ovarian cancer xenografts, respectively. Together, these data support the development of GDC-0941 as a potent, orally bioavailable inhibitor of phosphatidylinositide 3-kinase. GDC-0941 has recently entered phase I clinical trials.

The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis

“…In particular, we wanted to determine whether there is a difference between p110b inhibition as opposed to p110b deletion on oncogenic signals driven by MT or HER2/Neu. To investigate this, we isolated primary mammary tumor cells from tumorbearing MMTV-MT or MMTV-NeuT mice and subjected these cells to inhibitor studies using GDC-0941, a pan-PI3K inhibitor (Raynaud et al 2009); A66, a p110a-selective inhibitor (Sun et al 2010); and TGX-221, a p110b-selective inhibitor (Jackson et al 2005). We first determined that the amounts of p110a or p110b activity associated with the MT/p85 or NeuT/HER3/p85 complexes were not altered when cells were treated with these PI3K inhibitors (Supplemental Fig.…”

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

“…We used IC87114 as a p110␦ inhibitor (27)(28)(29). To inhibit all class I isoforms, we used the two compounds GDC-0941 (11,30,31) and ZSTK474 (32,33). In vitro, both compounds inhibit all class I isoforms with IC 50 values between 3 and 75 nM with some preference for p110␣ and p110␦ (Table 1).…”

“…For treatments with GDC-0941 or MLN1117, we used doses and formulations shown to provide anti-cancer efficacy in solid tumor xenograft models (31). 3 For treatment with IC87114, we used a dose and treatment protocol previously shown to reduce MZ B cell numbers in mice (28).…”

ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

“…Among the novel PI3K inhibitors, GDC-0941 and BEZ235 are the most intensively studied. Both compounds showed favorable efficacy in vitro and in vivo on various cancers without any obvious toxicity [23,[57][58][59][60] . In addition to the investigation of these compounds as single agents, combinations of PI3K inhibitors with other drug candidates that have different molecular targets were also reported.…”