Description
CCT251236 (1693731-40-6) is an inhibitor of the Heat Shock Transcription Factor 1 (HSF1) stress pathway (IC50 = 19 nM Inhibition HSF-1 mediated HSP72 induction, IC50 = 40 nM HSPA1A induction).1 It displayed efficacy in a human ovarian carcinoma xenograft mouse model (SK-OV 3 cells) and inhibited migration of WM266.4 melanoma cells @ 100 nM. CCT251236 showed high affinity for the protein pirin (Ki = 28 nM), but this target was not shown conclusively to be the cause of the anticancer activity. It also showed efficacy in vitro against primary patient-derived myeloma cells and H929 human myeloma xenograft models.2
Uses
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.
in vivo
CCT251236 (oral adminstation; 5 or 20 mg/kg) in nontumor bearing immunocompetent BALB/c mice exhibits free Cav0-24h value of 2.0 nM and 1.2 nM, respectively[2].
CCT251236 (oral adminstation; 20 mg/kg; 33 days) has a clear therapeutic efficacy in mice with a tumor growth inhibition (%TGI) of 70% based on final tumor volumes. After 33 days, the mean tumor weights decreases 64% when compares to control group. In addition, the compound’s basicity and high volume of distribution shows in tumor withtumor concentrations of CCT251236 as high as 940 nM[2].
| Animal Model: | Athymic mice with SK-OV-3 cells[2] |
| Dosage: | 20 mg/kg; 33 days |
| Administration: | Oral adminstation |
| Result: | Was efficacious in SK-OV-3 cell induced-tumor mice model. |
IC 50
HSP72: 19 nM (IC
50, SK-OV-3 cells)
References
[1] MATTHEW D. CHEESEMAN. Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen[J]. Journal of Medicinal Chemistry, 2016, 60 1: 180-201. DOI:
10.1021/acs.jmedchem.6b01055[2] JACQUELINE H L FOK. HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target.[J]. Clinical Cancer Research, 2018, 24 10: 2395-2407. DOI:
10.1158/1078-0432.ccr-17-1594
![N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-(2-(pyrrolidin-1-yl)ethoxy)quinoline-6-carboxamide Structure](https://www.chemicalbook.com/CAS/20200611/GIF/1693731-40-6.gif)
