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...

The scatter factor/hepatocyte growth factor (HGF)-c-Met axis is involved in the malignant phenotype of various tumor types via activation of a wide range of autocrine and paracrine processes. Autocrine activation of tumor cell c-Met receptors enhances tumor cell proliferation, angiogenesis, invasion/metastasis and resistance to apoptosis and cytotoxic therapies. In addition, tumor and stroma cell-derived HGF functions as a potent angiogenic factor. Therefore, the HGF-c-Met axis is critically involved in multiple facets of normal cellular growth and homeostasis and activated in a dysregulated manner in a variety of cancers. Consequently, inhibiting the HGF-c-Met axis would be anticipated to have potent anti-tumor effects in many cancers through multiple complimentary mechanisms including increased sensitivity to current cytotoxic chemo-and radiotherapies. The acceptance of c-Met as a tractable target for cancer therapy has fostered intensive drug discovery efforts across the pharmaceutical industry. This research has led to 20 published crystal structures (with and without ligands) that revealed two distinct binding modes for ATP-competitive inhibitors: Type I ligands which assumes a U shape geometry through interactions with both hinge and activation loop residue Y1230, and Type II ligands which adopt a more extended orientation, either binding a conventional DFG-out conformation or protein conformations with varying degrees of 'DFG-out' character. Nearly a dozen small molecule c-Met inhibitors have entered human clinical trials ranging from Type I inhibitors solely selective for c-Met to Type I inhibitors with broader kinase activities to Type II inhibitors with "spectrum selective" kinase activity. The identification, profiles and properties of these clinical candidates are summarized in this review.

Among the known angiogenic growth factors and cytokines implicated in the modulation of normal and pathological angiogenesis, the VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D) and their corresponding receptor tyrosine kinases [VEGFR-1 (Flt-1), VEGFR-2 (Flk-1, KDR), and VEGFR-3 (Flt-4)] play a paramount and indispensable role in regulating the multiple facets of the angiogenic and lymphangiogenic processes, as well as the induction of vascular permeability and inflammation. The receptor VEGFR-2/KDR is the principal one through which VEGFs exert their mitogenic, chemotactic, and vascular permeabilizing effects on the host vasculature. Increased expression of VEGFs by tumor cells and VEGFR-2/KDR and VEGFR-1/Flt-1 by the tumor-associated vasculature are a hallmark of a variety of human and rodent tumors in vivo and correlates with tumor growth rate, micro-vessel density/proliferation, tumor metastatic potential, and poorer patient prognosis in a variety of malignancies. Approaches to disrupting the VEGF/VEGFR signaling cascade range from biological agents (soluble receptors, anti-VEGF and anti-VEGFR-2 antibodies, and VEGF transcription inhibitors) to small molecule ATP competitive VEGFR inhibitors. Examples from this latter class that are currently in clinical development include compounds from distinct chemical classes such as: indolin-2-ones, anilinoquinazolines, anilinophthalazines, isothiazoles, indolo- and indenocarbazoles. The structure activity relationships, biochemical and pharmacological profile of optimized representatives from each of these classes constitute the subject matter of this review.

A series of novel 7-amino-1, 3,4,5-tetrahydrobenzo[b]azepin-2-one derivatives within the diaminopyrimidine class of kinase inhibitors were identified that target anaplastic lymphoma kinase (ALK). These inhibitors are potent against ALK in an isolated enzyme assay and inhibit autophosphorylation of the oncogenic fusion protein NPM-ALK in anaplastic large cell lymphoma (ALCL) cell lines. The lead inhibitor 15, which incorporates a bicyclo[2.2.1]hept-5-ene ring system in place of an aryl moiety, activates the pro-apoptotic caspases (3 and 7) and displays selective cytotoxicity against ALK-positive ALCL cells. Furthermore, 15 provides more than 40-fold selectivity against the structurally related insulin receptor, is orally bioavailable in multiple species, and displays in vivo antitumor efficacy when dosed orally in ALK-positive ALCL tumor xenografts in Scid mice.

The selection of compounds for use in high throughput biological assays is one of the critical factors that dictates the likelihood of detecting exploitable biological properties. In this paper, we present a process designed to deliver molecules that contain chemical functionality of immediate value in a lead discovery program, molecules that are sufficiently different from each other to ensure that redundancy of effort is avoided. The design process has already been implemented and used to add tens of thousands of reaction products to the Optiverse™ library