Identification of new aminoacid amides containing the imidazo[2,1-b]benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling.

Aix-Marseille Univ, IBDML, CNRS UMR 6216, Parc Scientifique de Luminy, Case 907, 13288 Marseille, France.
European Journal of Medicinal Chemistry (Impact Factor: 3.43). 11/2011; 47(1):239-54. DOI: 10.1016/j.ejmech.2011.10.051
Source: PubMed

ABSTRACT The Met receptor tyrosine kinase is a promising target in anticancer therapies for its role during tumor evolution and resistance to treatment. It is characterized by an unusual structural plasticity as its active site accepts different inhibitor binding modes. Such feature can be exploited to identify distinct agents targeting tumor dependence and/or resistance by oncogenic Met. Here we report the identification of bioactive agents, featuring a new 4-(imidazo[2,1-b]benzothiazol-2-yl)phenyl moiety, targeting cancer cells dependent on oncogenic Met. One of these compounds (7c; Triflorcas) impairs survival, anchorage-independent growth, and in vivo tumorigenesis, without showing side effects. Our medicinal chemistry strategy was based on an in-house Met-focused library of aminoacid-amide derivatives enriched through structure-based computer modeling, taking into account the Met multiple-binding-mode feature. Altogether, our findings show how a rational structure-based drug design approach coupled to cell-based drug evaluation strategies can be applied in medicinal chemistry to identify new agents targeting a given oncogenic-dependency setting.

  • [Show abstract] [Hide abstract]
    ABSTRACT: A series of novel aminopyridyl/pyrazinyl-substituted spiro[indoline-3,4'-piperidine]-2-ones were designed, synthesized, and tested in various in vitro/in vivo pharmacological and antitumor assays. 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1'-methylspiro[indoline-3,4'-piperidine]-2-one (compound 5b or SMU-B) was identified as a potent, highly selective, well-tolerated, and orally efficacious c-Met/ALK dual inhibitor, which showed pharmacodynamics effect by inhibiting c-Met phosphorylation in vivo and significant tumor growth inhibitions (>50%) in GTL-16 human gastric carcinoma xenograft models.
    ACS Medicinal Chemistry Letters 08/2013; 4(8):806-10. · 3.07 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: The receptor tyrosine kinase c-MET displays aberrant activation in the malignant phenotype of various tumors, and thus, has drawn considerable attention as drug target for cancer therapy. Many c-MET inhibitors are now under clinical investment, and one of them - Cabozantinib - has been approved by US FDA in 2012 for the treatment of medullary thyroid cancer, which further proved the feasibility of c-MET inhibition method in cancer therapy. Areas covered: This article briefly outlines the role of c-MET in oncogenesis and provides a broad overview of the assays used to characterize new inhibitors. Then, a series of representative small-molecule inhibitors of c-MET, especially from the published patent literature from 2011 to 2013, are recorded. Herein, the challenges in the kinase inhibitor design, such as the inhibitor selectivity and resistance mutations, are also discussed. Expert opinion: Up to now, at least 17 inhibitors of c-MET are under clinical evaluation, and several agents exhibit encouraging results. Thus, inhibiting c-MET signaling has major therapeutic value in cancer therapy. Focus on the selectivity of both types of inhibitors, with potent selectivity or multi-targets, have demonstrated antitumor efficacy. The network pharmacology and clinical trials integrated would provide powerful tools to further evaluate the superiority of both inhibitors in continued efficacy and toxicity.
    Expert Opinion on Therapeutic Patents 11/2013; · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The present study reports the preparation of a novel class of squalene conjugates with paclitaxel, podophyllotoxin, camptothecin and epothilone A. The obtained compounds are characterized by a squalene tail that makes them able to self-assemble in water, and by a drug unit connected via a disulfide-containing linker to secure the release inside the cell. All the obtained compounds were effectively able to self-assemble and to release the parent drug in vitro. Disulfide-containing paclitaxel-squalene derivative showed a similar biological activity when compared to the free drug. Immunofluorescence assay shows that this squalene conjugate enters A549 cells and stain microtubule bundles. The results described herein pave the way for different classes of squalene-based releasable nanoassemblies.
    European Journal of Medicinal Chemistry 10/2014; 85:179–190. · 3.43 Impact Factor


Available from
May 29, 2014

Similar Publications