CX-5461

CX-5461是一种rRNA synthesis（rRNA合成）抑制剂，选择性抑制Pol I驱动的rRNA转录，IC50为142 nM，对Pol II没有作用效果，抑制rRNA转录比DNA复制和蛋白翻译选择性高250到300倍。 CX-5461 is found to selectively inhibit rRNA synthesis (Pol I IC50=142 nM; Pol II IC50 > 25 μM; selectivity ~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 ~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. 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. Pidnarulex (CX-5461)是一种rRNA synthesis抑制剂，选择性抑制Pol I驱动的rRNA转录，在HCT-116，A375，和 MIA PaCa-2细胞中IC50为142 nM，对Pol II没有作用，对rRNA转录的抑制比对DNA复制和蛋白翻译的抑制选择性高250到300倍。

Target	Value
Pol I-driven transcription of rRNA (HCT-116, A375, MIA PaCa-2 cells)	142 nM

CX-5461能够选择性抑制HCT-116细胞中rRNA合成(Pol I IC50=142 nM；Pol II IC50 > 25 μM；选择性约200倍)。CX-5461对rRNA合成的选择性抑制在两种其他人类实体肿瘤细胞系，黑色素瘤 A375 (Pol I IC50 = 113 nM；Pol II IC50 > 25 μM)和胰腺癌MIA PaCa-2 (Pol I IC50=54 nM；Pol II IC50 ~25 mM)中得到证实。CX-5461对rRNA转录抑制作用的选择性是对DNA复制和蛋白质翻译的250~300倍。CX-5461对一组人类癌细胞系表现出光谱抗增殖活性，但是对非转化的人类细胞的作用活性很小。所有测试细胞系的中值EC50为147 nM，所有正常细胞系的EC50值大约为5, 000 nM。对HCT-116，A375，和MIA PaCa-2细胞系的抗增殖剂量响应评估的得到的EC50值分别为167，58，和74 nM。CX-5461通过p53-不依赖过程，诱导固体肿瘤细胞自吞噬或衰老，但不诱导细胞凋亡。

异种移植人固体肿瘤的小鼠模型中，CX-5461口服生物可利用，且在体内具有抗肿瘤活性。CX-5461显示出显著的MIA PaCa-2 TGI，在第31天，TGI 为69%，与gemcitabine (63% TGI)相当。Gemcitabine是一种阳性对照，其每3天以120 mg/kg腹腔内给药。同样的，CX-5461表现出显著的A375 TGI，第32天的TGI为79%。