CX-5461性質(zhì)、用途與生產(chǎn)工藝
CX-5461是一種rRNA synthesis（rRNA合成）抑制劑，選擇性抑制Pol I驅(qū)動的rRNA轉(zhuǎn)錄，IC50為142 nM，對Pol II沒有作用效果，抑制rRNA轉(zhuǎn)錄比DNA復(fù)制和蛋白翻譯選擇性高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)是一種rRNA synthesis抑制劑，選擇性抑制Pol I驅(qū)動的rRNA轉(zhuǎn)錄，在HCT-116，A375，和 MIA PaCa-2細(xì)胞中IC50為142 nM，對Pol II沒有作用，對rRNA轉(zhuǎn)錄的抑制比對DNA復(fù)制和蛋白翻譯的抑制選擇性高250到300倍。
| Target | Value |
Pol I-driven transcription of rRNA
(HCT-116, A375, MIA PaCa-2 cells)
|
142 nM
|
CX-5461能夠選擇性抑制HCT-116細(xì)胞中rRNA合成(Pol I IC50=142 nM；Pol II IC50 > 25 μM；選擇性約200倍)。CX-5461對rRNA合成的選擇性抑制在兩種其他人類實(shí)體腫瘤細(xì)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)中得到證實(shí)。CX-5461對rRNA轉(zhuǎn)錄抑制作用的選擇性是對DNA復(fù)制和蛋白質(zhì)翻譯的250~300倍。CX-5461對一組人類癌細(xì)胞系表現(xiàn)出光譜抗增殖活性，但是對非轉(zhuǎn)化的人類細(xì)胞的作用活性很小。所有測試細(xì)胞系的中值EC50為147 nM，所有正常細(xì)胞系的EC50值大約為5, 000 nM。對HCT-116，A375，和MIA PaCa-2細(xì)胞系的抗增殖劑量響應(yīng)評估的得到的EC50值分別為167，58，和74 nM。CX-5461通過p53-不依賴過程，誘導(dǎo)固體腫瘤細(xì)胞自吞噬或衰老，但不誘導(dǎo)細(xì)胞凋亡。
異種移植人固體腫瘤的小鼠模型中，CX-5461口服生物可利用，且在體內(nèi)具有抗腫瘤活性。CX-5461顯示出顯著的MIA PaCa-2 TGI，在第31天，TGI 為69%，與gemcitabine (63% TGI)相當(dāng)。Gemcitabine是一種陽性對照，其每3天以120 mg/kg腹腔內(nèi)給藥。同樣的，CX-5461表現(xiàn)出顯著的A375 TGI，第32天的TGI為79%。
CX-5461
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