Target Validation Information
Target ID T16016
Target Name C-C chemokine receptor type 1
Target Type
Clinical Trial
Drug Potency against Target MLN3897 Drug Info IC50 = 0.8 nM [552730]
COSALANE Drug Info IC50 = 260 nM [525947]
Action against Disease Model MLN3897 MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. MLN3897 demonstrates significant impairment of OC formation (by 40%) and function (by 70%), associated with decreased precursor cell multinucleation and down-regulation of c-fos signaling. OCs secrete high levels of CCL3, which triggers MM cell migration; conversely, MLN3897 abrogates its effects by inhibiting Akt signaling. Moreover, MM cell-to-OC adhesion was abrogated by MLN3897, thereby inhibiting MM cell survival and proliferation. [552730] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Because lung concentrations of macrophage inflammatory protein-1alpha and RANTES were significantly elevated after A. f uMigatus-sensitized mice received an intrapulmonary challenge with A. f uMigatus spores or conidia, the present study addressed the role of their receptor, C-C chemokine receptor 1 (CCR1), in this model. A. f uMigatus-sensitized CCR1 wild-type (+/+) and CCR1 knockout (-/-) mice exhibited similar increases in ser uM IgE and polymorphonuclear leukocyte n uMbers in the bronchoalveolar lavage. Airway hyperresponsiveness was prominent in both groups of mice at 30 days after an intrapulmonary challenge with A. f uMigatus spores or conidia. However, whole lung levels of IFN-gamma were significantly higher whereas IL-4, IL-13, and Th2-inducible chemokines such as C10, eotaxin, and macrophage-derived chemokine were significantly lower in whole lung samples from CCR1-/- mice compared with CCR1+/+ mice at 30 days after the conidia challenge. Likewise, significantly fewer goblet cells and less subepithelial fibrosis were observed around large airways in CCR1-/- mice at the same time after the conidia challenge. Thus, these findings demonstrate that CCR1is a major contributor to the airway remodeling responses that arise from A. f uMigatus-induced allergic airway disease. [552730]
References
Ref 552730MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. Blood. 2007 Nov 15;110(10):3744-52. Epub 2007 Aug 22.
Ref 552730MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. Blood. 2007 Nov 15;110(10):3744-52. Epub 2007 Aug 22.
Ref 525947Bioorg Med Chem Lett. 2001 Jan 8;11(1):59-62.Inhibition of RANTES/CCR1-mediated chemotaxis by cosalane and related compounds.

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