An inhibitor of Hsf1-mediated transcription
CCT251236 is an orally available pirin ligand from a heat shock transcription factor 1 (hsf1) phenotypic screen with an IC50 of 19 nM for inhibition of HSF1-mediated HSP72 induction.
CCT251236 displays the desired balance of in vitro properties, while maintaining excellent cellular activity with an IC50 of 19 nM. The free GI50 in SK-OV-3 cells is 1.1 nM. Western blotting confirms that CCT251236 blocks the HSF1-mediated induction of both HSP72 and HSP27 as representative heat shock proteins, following treatment with the HSP90 inhibitor 17AAG. Also, qPCR analysis demonstrates that CCT251236 inhibits the induction of HSP72 at the mRNA level, clearly blocking the induction of HSPA1A gene expression with an IC50 of 40 nM[1].
CCT251236 possesses low total blood clearance (10% hepatic blood flow) and moderate oral bioavailability, with a half-life sufficient to allow once-a-day dosing. Clear therapeutic efficacy is observed with CCT251236, with a tumor growth inhibition of 70% based on final tumor volumes[1].
参考文献:
[1]. Cheeseman MD, et al. Discovery of a Chemical Probe Bisamide (CCT251236): An OrallyBioavailable Efficacious Pirin Ligand from a Heat ShockTranscription Factor 1 (HSF1) Phenotypic Screen. J Med Chem. 2017 Jan 12;60(1):180-201.
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Animal experiment: |
Mice: SK-OV-3 cells are injected subcutaneously into athymic mice for tumor formation. Once tumors are established, the mice are randomized into treatment and control groups and are dosed orally once-a-day with either vehicle or 20 mg/kg of CCT251236. Tumor volumes and mouse body weights are measured throughout and tumor weights are measured at the end of the study, while total tumor concentrations are measured 2 and 6 hours post final dose[1]. |
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参考文献: [1]. Cheeseman MD, et al. Discovery of a Chemical Probe Bisamide (CCT251236): An OrallyBioavailable Efficacious Pirin Ligand from a Heat ShockTranscription Factor 1 (HSF1) Phenotypic Screen. J Med Chem. 2017 Jan 12;60(1):180-201. |
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