CT-721, a Potent Bcr-Abl Inhibitor, Exhibits Excellent In Vitro and In Vivo Efficacy in the Treatment of Chronic Myeloid Leukemia.

Kinase inhibitors that target Bcr-Abl are highly effective in the treatment of chronic myeloid leukemia (CML). However, these inhibitors are often invalidated due to the drug resistance. Therefore, the discovery and development of novel Bcr-Abl inhibitors is required to overwhelm the drug resistance in the treatment of CML resistant to the currently used first-line Bcr-Abl inhibitors. Herein we have described a newly developed Bcr-Abl inhibitor CT-721, which displayed potent inhibitory effects on wild-type and T315I mutant Bcr-Abl. It functioned as a typically ATP-competitive inhibitor, superior to other existing Bcr-Abl inhibitors. CT-721 also demonstrated time-dependent inhibition of Bcr-Abl activation and the resultant downstream signaling transduction pathways in Bcr-Abl positive cells. Furthermore, CT-721 induced cell apoptosis and cell cycle arrest, and efficaciously inhibited tumor growth in Bcr-Abl-expressed K562 and KU812 xenograft models in a mechanism-based manner. Further PK/PD studies revealed a positive in vivo correlation between the compound concentration and inhibition of Bcr-Abl activity. Taken together, CT-721 is a potent and time-dependent Bcr-Abl kinase inhibitor, and has shown strong in vitro and in vivo anti-CML activities with a favorable pharmacokinetic profile, differentiating it from other Bcr-Abl kinase inhibitors already approved and current in development for the treatment of CML.

Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors.

The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer.

Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors.

Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg.

Discovery of pyrrolopyrimidine inhibitors of Akt.

The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.

Effects of sinusoidal magnetic field observed on cell proliferation, ion concentration, and osmolarity in two human cancer cell lines.

Low frequency magnetic fields have previously been shown to affect cell functions. In this article, the effects of 20 mT, 50 Hz sinusoidal magnetic field on cell proliferation, ion concentration, and osmolarity in two human cancer cell lines (HL-60 and SK-Hep-1) were investigated. Inhibition of cell growth was observed. On the other hand, the exposure also increased the Na+, K+ ion concentration and osmolarity in cell supernatant compared to the control group. To our knowledge, this is the first study on cancer cells where magnetic fields affect osmolarity in cell supernatant. In addition, a model of cells exposed to the oscillating magnetic field is described as well as the characteristics of ions in and out of cells. The experimental data appears to be consistent with the theoretical analysis. The results are also discussed in terms of the relationships among cell growth, ion concentration, and osmolarity. Magnetic field inhibitions of cell growth in vitro may relate to changes in cell ion concentration and osmolarity.

The discovery of a selective, high affinity A(2B) adenosine receptor antagonist for the potential treatment of asthma.

Adenosine has been suggested to play a role in asthma, possibly via activation of A(2B) adenosine receptors on mast cells and other pulmonary cells. We describe our initial efforts to discover a xanthine based selective A(2B) AdoR antagonist that resulted in the discovery of CVT-5440, a high affinity A(2B) AdoR antagonist with good selectivity (A(2B) AdoR K(i)=50 nM, selectivity A(1)>200: A(2A)>200: A(3)>167).

Highly Enantioselective Hydrogenation of Cyclic Enol Acetates Catalyzed by a Rh-PennPhos Complex.

The electron-rich and conformationally rigid (R,S,R,S)-Me-PennPhos ligand (shown schematically) appears to chelate rhodium and form well-defined chiral pockets. This allows, for example, efficient differentiation between the two enantiotopic approaches available to a substrate in a hydrogenation reaction. The Rh-Me-PennPhos complex is the first catalyst for the highly enantioselective asymmetric hydrogenation of cyclic enol acetates. For example, 3,4-dihydronaphth-1-yl acetate can be hydrogenated with up to 99% ee.

Highly Enantioselective Hydrogenation of Simple Ketones Catalyzed by a Rh-PennPhos Complex.

Even alkyl methyl ketones undergo asymmetric hydrogenation with high enantioselectivity when a rhodium complex of the conformationally rigid chiral ligand 1 (Me-PennPhos; R=CH3 ) is used as the catalyst. Basic additives such as 2,6-lutidine contribute to the achievement of high enantiomeric excesses.