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
protein kinase MPS1 is a crucial component of the spindle assembly
checkpoint signal and is aberrantly overexpressed in many human cancers.
MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal
instability and aneuploidy. PTEN-deficient breast tumor cells are
particularly dependent upon MPS1 for their survival, making it a target
of significant interest in oncology. We report the discovery and optimization
of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based
design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes
an inactive conformation of MPS1 with the activation loop ordered
in a manner incompatible with ATP and substrate-peptide binding; it
displays a favorable oral pharmacokinetic profile, shows dose-dependent
inhibition of MPS1 in an HCT116 human tumor xenograft model, and is
an attractive tool compound to elucidate further the therapeutic potential
of MPS1 inhibition.
Optimization of the imidazo[4,5-b]pyridine-based
series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora
kinases (Aurora-A Kd = 7.5 nM, Aurora-B Kd = 48 nM), FLT3 kinase (Kd = 6.2 nM), and FLT3 mutants including FLT3-ITD (Kd = 38 nM) and FLT3(D835Y) (Kd = 14 nM). FLT3-ITD causes constitutive FLT3 kinase
activation and is detected in 20–35% of adults and 15% of children
with acute myeloid leukemia (AML), conferring a poor prognosis in
both age groups. In an in vivo setting, 27e strongly
inhibited the growth of a FLT3-ITD-positive AML human
tumor xenograft (MV4–11) following oral administration, with
in vivo biomarker modulation and plasma free drug exposures consistent
with dual FLT3 and Aurora kinase inhibition. Compound 27e, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was
selected as a preclinical development candidate for the treatment
of human malignancies, in particular AML, in adults and children.
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