CX-5461

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

CX-5461 是第一个有效的、选择性的、口服生物可利用的 RNA 聚合酶 I 抑制剂。

CX-5461 is the first potent, selective, orally bioavailable inhibitor of RNA polymerase I, selectively inhibits rRNA synthesis in HCT-116 cells with IC50 of 142 nM, 200-fold selectivity over Pol II; inhibits the initiation stage of rRNA synthesis and induces both senescence and autophagy, but not apoptosis, through a p53-independent process in solid tumor cell lines; demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models.Solid Tumors Phase 2 Clinical.

CX-5461 is a potent and orally bioavailable inhibitor of Pol I-mediated rRNA synthesis, with IC50s of 142 nM in HCT-116, 113 nM in A375, and 54 nM in MIA PaCa-2 cells, and shows little or no effect on Pol II (IC50, ≥25 μM). CX-5461 has modest inhibition on DNA replication and protein translation. CX-5461 also exhibits broad antiproliferative activity against a panel of human cancer cell lines, with a mean EC50 of 147 nM, but has minimal effect on viability of nontransformed human cells, with EC50 values of appr 5000 nM. EC50s of CX-5461 for HCT-116, A375, and MIA PaCa-2 cell lines are 167, 58, and 74 nM, respectively. CX-5461 induces autophagy and senescence in solid tumor cancer cells, rather than apoptosis, through a p53-independent process. 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.

CX-5461 displays antitumor activity against human solid tumors in murine xenograft models. CX-5461 (50 mg/kg, p.o.) shows significant MIA PaCa-2 growth inhibition with TGI equal to 69% on day 31 and 79% TGI on A375 on day 32. CX-5461 (50 mg/kg, p.o.) inhibits the Eμ-Myc tumor cells with 84% repression in Pol I transcription at 1 hr posttreatment in C57BL/6 mice. CX-5461 also induces a rapid reduction in tumor burden in the lymph nodes and a concomitant reduction of spleen size to within the normal range.

CX 5461 | CX5461

Cell Cycle/DNA Damage

DNA/RNA Synthesis

PolI-driventranscriptionofrRNA

Cancer

Solid Tumors

1138549-36-6

513.61

C27H27N7O2S

>98% (HPLC)

DMSO: < 5.3 mg/mL

O=C(C1=C(SC2=CC=CC=C23)N3C4=C(C=CC(N5CCN(C)CCC5)=N4)C1=O)NCC6=NC=C(C)N=C6

5H-Benzothiazolo[3,2-a][1,8]naphthyridine-6-carboxamide, 2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-N-[(5-methyl-2-pyrazinyl)methyl]-5-oxo-

(-20℃)

With Ice Pack

≥ 2 years