The roles of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of anaplastic large-cell lymphoma (ALCL) have been well defined; nevertheless, the notion that ALK is a molecular target for the therapeutic modulation of ALK ؉ ALCL has not been validated thus far. Select fused pyrrolocarbazole (FP)-derived small molecules with ALK inhibitory activity were used as pharmacologic tools to evaluate whether functional ALK is essential for the prolifera- IntroductionChromosomal translocations occur frequently in a select group of human cancers, including most lymphomas, leukemias, and sarcomas. Individual translocations have shown a high degree of specificity for particular cancer types and the presence of a particular translocation often correlates well with clinical behavior and outcome for specific types of cancer. 1 Consequently, therapies directed at molecular targets dysregulated by tumor-specific genetic aberrations will potentially provide more effective and less toxic therapies than conventional chemotherapy. 1,2 Anaplastic large-cell lymphomas (ALCLs) comprise a group of non-Hodgkin lymphomas (NHLs) that are usually of T-cell origin and often present with extranodal disease, especially the skin, and are characterized by the expression of the CD30/Ki-1 antigen. Roughly 2500 to 3000 new cases of ALCLs are diagnosed in the United States each year and 50% to 60% of these ALCLs are associated with a specific t(2;5) (p23;q35) chromosome translocation. 4,5 The genes altered in the t(2;5) translocation contain the N-terminal portion of nucleophosmin (NPM) gene, a nuclear phosphoprotein, fused to the catalytic domain of anaplastic lymphoma kinase (ALK) gene. ALK is a cell-membrane-spanning receptor tyrosine kinase and a member of the insulin receptor superfamily. Although the precise physiologic function and regulation of ALK have not been well defined, the NPM-ALK fusion gene encodes for an 80-kDa NPM-ALK chimeric oncoprotein with constitutively active ALK tyrosine kinase activity, which plays a key role in lymphomagenesis by the aberrant phosphorylation of multiple intracellular substrates downstream of NPM-ALK. 4,5 Subsequently, other fusion partners of ALK were also reported in ALCL, and dysregulated expression and constitutive activation of the ALK protein was demonstrated in approximately 60% to 70% of ALCLs, termed ALK ϩ lymphomas. 4,[6][7][8] Preclinical experimental data have demonstrated that the aberrant expression of constitutively active ALK is directly implicated in the pathogenesis of ALCL and that ALK down-regulation or inhibition of ALK-mediated pathways can markedly impair the growth of ALK ϩ lymphoma cells. 9-15 Currently there is no optimal therapeutic regimen for ALK ϩ ALCL. Doxorubicin-based combination chemotherapy has limited effectiveness, resulting in a substantial number of patients with ALK ϩ ALCL with a poor outcome, either failing to enter remission or relapsing within a few months from the start of treatment. 3 Thus, optimal and more effective therapeu...

Optimization of a novel series of pyridazin-3-one histamine H(3) receptor (H(3)R) antagonists/inverse agonists identified 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (8a, CEP-26401; irdabisant) as a lead candidate for potential use in the treatment of attentional and cognitive disorders. 8a had high affinity for both human (K(i) = 2.0 nM) and rat (K(i) = 7.2 nM) H(3)Rs with greater than 1000-fold selectivity over the hH(1)R, hH(2)R, and hH(4)R histamine receptor subtypes and against an in vitro panel of 418 G-protein-coupled receptors, ion channels, transporters, and enzymes. 8a demonstrated ideal pharmaceutical properties for a CNS drug in regard to water solubility, permeability and lipophilicity and had low binding to human plasma proteins. It weakly inhibited recombinant cytochrome P450 isoforms and human ether-a-go-go-related gene. 8a metabolism was minimal in rat, mouse, dog, and human liver microsomes, and it had good interspecies pharmacokinetic properties. 8a dose-dependently inhibited H(3)R agonist-induced dipsogenia in the rat (ED(50) = 0.06 mg/kg po). On the basis of its pharmacological, pharmaceutical, and safety profiles, 8a was selected for preclinical development. The clinical portions of the single and multiple ascending dose studies assessing safety and pharmacokinetics have been completed allowing for the initiation of a phase IIa for proof of concept.

A substantial body of evidence supports the utility of antiangiogenesis inhibitors as a strategy to block or attenuate tumor-induced angiogenesis and inhibition of primary and metastatic tumor growth in a variety of solid and hematopoietic tumors. Given the requirement of tumors for different cytokine and growth factors at distinct stages of their growth and dissemination, optimal antiangiogenic therapy necessitates inhibition of multiple, complementary, and nonredundant angiogenic targets. 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (11b, CEP-11981) is a potent orally active inhibitor of multiple targets (TIE-2, VEGF-R1, 2, and 3, and FGF-R1) having essential and nonredundant roles in tumor angiogenesis and vascular maintenance. Outlined in this article are the design strategy, synthesis, and biochemical and pharmacological profile for 11b, which completed Phase I clinical assessing safety and pharmacokinetics allowing for the initiation of proof of concept studies.

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