| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T97947 | ||||
| Target Name | Guanylyl cyclase C | ||||
| Target Type | Successful |
||||
| Drug Potency against Target | Linaclotide | Drug Info | EC50 = 400 nM | [552548] | |
| Action against Disease Model | Linaclotide | Linaclotide exhibited high affinity and pH-independent binding (K(i): 1.23-1.64 nM) to guanylate cyclase C receptors on h uMan colon carcinoma T84 cells and concomitantly, linaclotide binding resulted in a significant, concentration-dependent acc uMulation of intracellular cyclic guanosine-3', 5'-monophosphate (cGMP) (EC50:99 nM). Linaclotide was stable after 3 h incubation in simulated gastric fluid (pH 1) and similarly, was completely resistant to hydrolysis by pepsin. | [553072] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | Intestinal t uMorigenesis was examined in wild-type guanylyl cyclase C (GCC)(Gcc(+/+)) and GCC-deficient (Gcc(-/-)) mice carrying mutations in Apc (Apc(Min/+)) or exposed to thecarcinogen azoxymethane. Markers of DNA damage, loss of Apc heterozygosity, and beta-catenin mutations were used to assess genomic integrity. Hyperproliferation was explored using Ki67 and cell cyclemarkers. Apoptosis was quantified by transferase biotin-dUTP nick end labeling analysis.In colons of Apc(Min/+) mice, deletion of Gcc increased t uMor incidence and multiplicity, reflecting uncoupling of loss of genomic integrity and compensatory apoptosis. Conversely, in the small intestine, elimination of Gcc increased t uMorigenesis by enhancing proliferation without altering genomic integrity. Moreover, these distinct but mutually reinforcing mechanisms collaborate in azoxymethane-exposed mice, and deletion of Gcc increased t uMor initiation and growth associated with hypermutation and hyperproliferation, respectively, in conjunction with attenuated apoptosis.GCC suppresses t uMor initiation and growth by maintaining genomic integrity and restricting proliferation. This previously unrecognized role of GCC in inhibiting t uMorigenesis, together with the invariant disruption in guanylin and uroguanylin expression early in carcinogenesis, and the uniform over-expression of GCC by t uMors, underscores the potential of oral administration of GCC ligands for targeted prevention and therapy of colorectal cancer | [552548] | |||
| References | |||||
| Ref 552548 | Positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (mGluR2). Curr Top Med Chem. 2005;5(9):869-84. | ||||
| Ref 553072 | Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit. Eur J Pharmacol. 2010 Dec 15;649(1-3):328-35. doi: 10.1016/j.ejphar.2010.09.019. Epub 2010 Sep 20. | ||||
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