| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T84634 | ||||
| Target Name | Cytochrome P450 26 | ||||
| Target Type | Clinical Trial |
||||
| Drug Potency against Target | Rambazole | Drug Info | IC50 = 5 nM | [529651] | |
| 4-((+/-)-(1H-imidazol-1-yl)-(E)-retinoic acid | Drug Info | IC50 = 2.4 nM | [527351] | ||
| 4-((+/-)-(1H-imidazol-1-yl)-(E)-methylretinoate | Drug Info | IC50 = 40 nM | [527351] | ||
| Rambazole | Drug Info | IC50 = 4 nM | |||
| LIAROZOLE | Drug Info | IC50 = 7000 nM | [529651] | ||
| Action against Disease Model | Rambazole | Talarozole (R115866), a selective inhibitor of P450-mediated all-trans retinoic acid for the treatment of psoriasis and acne. Silencing of the CYP26B1 gene expression or reduction of CYP26B1 enzymatic activity by using siRNA or the inhibitor R115866, respectively, increased atRA-mediated signaling and resulted in decreased cell proliferation. The CYP26 inhibitor also inducedexpression of atRA-responsive genes. Therefore, atRA-induced CYP26 expression accelerated atRA inactivation in AOSMCs, giving rise to an atRA-CYP26 feedback loop. Inhibition of this loop with a CYP26inhibitor increased retinoid signaling. | [553057] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | We have previously reported that a cytochrome P450, CYP6BG1, from Plutella xylostella was found to be overexpressed in 4th instars of a permethrin resistant strain and induciblein the susceptible counterpart. The findings suggested potential involvement of CYP6BG1 in permethrin resistance, hence warranted a functional analysis. To assess the functional link of the gene to permethrin resistance, we adopted RNA interference-mediated gene silencing (RNAi) by dsRNA droplet feeding. Here, real time PCR analyses show that oral delivery of dsRNA can efficiently reduce the expression of CYP6BG1. Knockdown of CYP6BG1 transcript was evident in midgut and larval tissues enclosed in carcass. As a consequence of knockdown, a significant reduction in resistance of larvae fed CYP6BG1 dsRNA was observed after 24 and 48 h of exposure to permethrin. In addition, CYP6BG1 dsRNA feeding to larvae led to reduced total P450 activities of microsomal preparations toward model substratesp-nitroanisole and benzyloxyresorufin. These results indicate that the overexpressed CYP6BG1 participate in enhanced metabolism of permethrin, thereby, resistance. The knockdown of a non-overexpressed P450, CYP6BF1v4, from the same resistant P. xylostella strain did not lead to changes in the level of resistance to permethrin, supporting further the specific involvement of CYP6BG1 in the resistance. | [529651] | |||
| References | |||||
| Ref 529651 | Bioorg Med Chem. 2008 Sep 1;16(17):8301-13. Epub 2007 Jun 29.Novel azolyl-(phenylmethyl)]aryl/heteroarylamines: potent CYP26 inhibitors and enhancers of all-trans retinoic acid activity in neuroblastoma cells. | ||||
| Ref 527351 | J Med Chem. 2004 Dec 30;47(27):6716-29.Novel retinoic acid metabolism blocking agents endowed with multiple biological activities are efficient growth inhibitors of human breast and prostate cancer cells in vitro and a human breast tumor xenograft in nude mice. | ||||
| Ref 527351 | J Med Chem. 2004 Dec 30;47(27):6716-29.Novel retinoic acid metabolism blocking agents endowed with multiple biological activities are efficient growth inhibitors of human breast and prostate cancer cells in vitro and a human breast tumor xenograft in nude mice. | ||||
| Ref 553057 | CYP26B1 plays a major role in the regulation of all-trans-retinoic acid metabolism and signaling in human aortic smooth muscle cells. J Vasc Res. 2011;48(1):23-30. doi: 10.1159/000317397. Epub 2010 Jul 6. | ||||
| Ref 529651 | Bioorg Med Chem. 2008 Sep 1;16(17):8301-13. Epub 2007 Jun 29.Novel azolyl-(phenylmethyl)]aryl/heteroarylamines: potent CYP26 inhibitors and enhancers of all-trans retinoic acid activity in neuroblastoma cells. | ||||
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