CX-5461 | CAS:1138549-36-6

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Name:CX-5461; 
Cat. No. :CS-0568
CAS No. :1138549-36-6
Formula:C27H27N7O2S
M. Wt. : 513.61
Solubility:DMSO:

CX-5461 is an inhibitor of rRNA synthesis, and selectively inhibits Pol I-driven transcription of rRNA with IC50 of 142 nM in HCT-116, A375, and MIA PaCa-2 cells, with no effect on Pol II, and possesses 250- to 300-fold selectivity for inhibition of rRNA transcription versus DNA replication and protein translation.IC50 & Target: IC50: 142 nM (rRNA synthesis)In Vitro: CX-5461 is found to selectively inhibit rRNA synthesis (Pol I IC50=142 nM; Pol II IC50 > 25 μM; selectivity appr 200-fold) in the HCT-116 cells. Selective inhibition of rRNA synthesis by CX-5461 is confirmed in two other human solid tumor cell lines; melanoma A375 (Pol I IC50=113 nM; Pol II IC50 > 25 μM) and pancreatic carcinoma MIA PaCa-2 (Pol I IC50=54 nM; Pol II IC50 appr 25 mM). CX-5461 possesses 250- to 300-fold selectivity for inhibition of rRNA transcription versus DNA replication and protein translation. CX-5461 exhibits broad antiproliferative potency in a panel of cancer cell lines in human cancer cell lines, but has minimal effect on viability of nontransformed human cells. The median EC50 across all tested cell lines is 147 nM, yet all normal cell lines have EC50 values of approximately 5, 000 nM. Evaluation of the antiproliferative dose response for HCT-116, A375, and MIA PaCa-2 cell lines yield EC50 values of 167, 58, and 74 nM. CX-5461 induces autophagy and senescence in solid tumor cancer cells, rather than apoptosis, through a p53-independent process[1]. Eμ-Myc lymphoma cells from tumor-bearing mice are exquisitely sensitive to CX-5461 with an IC50 of 27.3 nM±8.1 nM for Pol I transcription after 1 hr and IC50 of 5.4 nM ±2.1 nM for cell death after 16 hr. CX-5461 activates p53 via the nucleolar stress response in Eμ-MycLymphoma Cells[2].In Vivo: CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. CX-5461 demonstrates significant MIA PaCa-2 TGI with TGI equal to 69% on day 31, comparable to that of gemcitabine (63% TGI). Gemcitabine is a positive control which is administered intraperitoneally once every 3 days at 120 mg/kg. Likewise, CX-5461 demonstrates significant A375 TGI with TGI equal to 79% on day 32[1]. CX-5461 (50 mg/kg) inhibits the Eμ-Myc tumor cells with 84% repression in Pol I transcription at 1 hr posttreatment. CX-5461 induces a rapid reduction in tumor burden in the lymph nodes and a concomitant reduction of spleen size to within the normal range[2].

Drygin D et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res. 2011 Feb 15;71(4):1418-30. Bywater MJ, et al. Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53.Cancer Cell. 2012 Jul 10;22(1):51-65.