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The high expression of proviral insertion site of Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role in promoting cell survival and proliferation while suppressing apoptosis. The three isoforms of Pim protein appear largely redundant in their oncogenic functions. Thus, a pan-Pim kinase inhibitor is highly desirable. However, cell active pan-Pim inhibitors have proven difficult to develop because Pim-2 has a low Km for ATP and therefore requires a very potent inhibitor to effectively block the kinase activity at cellular ATP concentrations. Herein, we report a series of quinazolinone-pyrrolopyrrolones as potent and selective pan-Pim inhibitors. In particular, compound 17 is orally efficacious in a mouse xenograft model (KMS-12 BM) of multiple myeloma, with 93% tumor growth inhibition at 50 mg/kg QD upon oral dosing. [ABSTRACT FROM AUTHOR]

Abstract: Ullmann ether synthesis was conducted on a variety of chloro-heterocycles with different phenols using optimized conditions involving copper powder and cesium carbonate. On many substrates, microwave heating afforded higher yields in significantly shorter reaction times compared to conventional heating conditions. These findings provide a facile method for aryl ether synthesis from chloropyridines, chloroquinolines, and chlorobenzothiazoles. [Copyright &y& Elsevier]

The phosphoinositide 3-kinase family catalyzes the phosphorylationof phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate,a secondary messenger which plays a critical role in important cellularfunctions such as metabolism, cell growth, and cell survival. Ourefforts to identify potent, efficacious, and orally available phosphatidylinositol3-kinase (PI3K) inhibitors as potential cancer therapeutics have resultedin the discovery of 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine(1). In this paper, we describe the optimization of compound 1, which led to the design and synthesis of pyridyltriazine 31, a potent pan inhibitor of class I PI3Ks with a superiorpharmacokinetic profile. Compound 31was shown to potentlyblock the targeted PI3K pathway in a mouse liver pharmacodynamic modeland inhibit tumor growth in a U87 malignant glioma glioblastoma xenograftmodel. On the basis of its excellent in vivo efficacy and pharmacokineticprofile, compound 31was selected for further evaluationas a clinical candidate and was designated AMG 511. [ABSTRACT FROM AUTHOR]

A highly selective series of inhibitors of the classI phosphatidylinositol3-kinases (PI3Ks) has been designed and synthesized. Starting fromthe dual PI3K/mTOR inhibitor 5, a structure-based approachwas used to improve potency and selectivity, resulting in the identificationof 54as a potent inhibitor of the class I PI3Ks withexcellent selectivity over mTOR, related phosphatidylinositol kinases,and a broad panel of protein kinases. Compound 54demonstrateda robust PD–PK relationship inhibiting the PI3K/Akt pathwayin vivo in a mouse model, and it potently inhibited tumor growth ina U-87 MG xenograft model with an activated PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

The phosphoinositide 3-kinase (PI3K) family catalyzes the ATP-dependent phosphorylation of the 3′-hydroxyl group of phosphatidylinositols and plays an important role in cell growth and survival. There is abundant evidence demonstrating that PI3K signaling is dysregulated in many human cancers, suggesting that therapeutics targeting the PI3K pathway may have utility for the treatment of cancer. Our efforts to identify potent, efficacious, and orally available PI3K/mammalian target of rapamycin (mTOR) dual inhibitors resulted in the discovery of a series of substituted quinolines and quinoxalines derivatives. In this report, we describe the structure–activity relationships, selectivity, and pharmacokinetic data of this series and illustrate the in vivo pharmacodynamic and efficacy data for a representative compound. [ABSTRACT FROM AUTHOR]

Abstract: DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520. [Copyright &y& Elsevier]