| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T25315 | ||||
| Target Name | C-X-C chemokine receptor type 3 | ||||
| Target Type | Discontinued |
||||
| Drug Potency against Target | T487 | Drug Info | IC50 = 13.27 nM | ||
| T487 | Drug Info | IC50 = 240 nM | [530278] | ||
| Action against Disease Model | T487 | Treatment of osteosarcoma cells in vitro with AMG487, ananomolar CXCR3 antagonist, led to decreased migration, decreased matrix metalloproteinase activity, decreased proliferation/survival and increased caspase-independent death. | [552708] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | CXCR3 knockout (CXCR3-/-) mice were used. Differences in airspace enlargement, mRNA expression of matrix metalloproteinases (MMPs), transforming growth factor (TGF) beta1, CXCL10 in lung homogenates, and CXCL10 content in bronchoalveolar lavage (BAL) fluids and homogenates were compared between CXCR3-/- mice and wild-type (WT) mice three days after three-day CS exposures.Thelinear intercept was significantly less in CXCR3-/- mice than in WT mice (30.1+/-0.9 microm vs 40.3+/-2.4 microm, P<0.01). Morphologically, collagen was deposited less around airways and vessels in CXCR3-/- mice. The lung hydroxyproline content was significantly lower in CXCR3-/- mice than in WT mice (6.0+/-1.0 microg/mL vs 12.0+/-1.6 microg/mL, P<0.05). Profoundly lower mRNA expression of MMP2, MMP12, TGF beta 1, and CXCL10 was seen in lung homogenates from CXCR3-/- mice. CXCL10 concentrations in BAL fluid and lung homogenates were significantly lower in CXCR3-/- mice than in WT mice (BAL fluid: 19.3+/-1.4 pg/mL vs 24.8+/-1.6 pg/mL, P<0.05; lung homogenates: 76.6+/-7.0 pg/mL vs 119.5+/-15.9 pg/mL, P<0.05).CXCR3 is important in mediating lung tissue damage and airway remodeling following a short-term CS insult, possibly through up-regulation of CXCL10 and inducement of mRNA expression of MMPs. Targeting CXCR3 may be helpful for prevention of CS-induced pulmonary pathology | [552708] | |||
| References | |||||
| Ref 552708 | Synthesis and structure-activity relationships of 3H-quinazolin-4-ones and 3H-pyrido[2,3-d]pyrimidin-4-ones as CXCR3 receptor antagonists. Arch Pharm (Weinheim). 2007 Jun;340(6):281-91. | ||||
| Ref 530278 | Bioorg Med Chem Lett. 2009 Sep 1;19(17):5114-8. Epub 2009 Jul 10.Optimization of a series of quinazolinone-derived antagonists of CXCR3. | ||||
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.