935881-37-1
中文名稱
AR-42
英文名稱
AR-42
CAS
935881-37-1
分子式
C18H20N2O3
分子量
312.363
MOL 文件
935881-37-1.mol
更新日期
2024/10/09 14:12:00
935881-37-1 結(jié)構(gòu)式
基本信息
中文別名
化合物AR42(S)-N-羥基-4-(3-甲基-2-苯基丁酰胺基)苯甲酰胺
(S)-(+)-N-羥基-4-(3-甲基-2-苯基丁酰氨基)苯甲酰胺
英文別名
AR-42CS-15
OSU-HD
HDAC-42
OSU-HDAC42
(S)-HDAC 42
NSC-D736012
AR-42 (HDAC-42)
(S)-HDAC-42,AR-42
AR-42 (OSU-HDAC42)
所屬類別
生物化工：HDAC 抑制劑物理化學(xué)性質(zhì)
密度1.223
儲(chǔ)存條件Inert atmosphere,Store in freezer, under -20°C
溶解度insoluble in EtOH; insoluble in H2O; ≥15.62 mg/mL in DMSO
酸度系數(shù)(pKa)8.94±0.10(Predicted)
形態(tài)粉末
顏色White to light brown
常見問(wèn)題列表
生物活性
AR-42是一種HDAC抑制劑，IC50為30 nM。Phase 1。體外研究
AR-42 treatment induces histone hyperacetylation and p21WAF/CIP1 overexpression, and inhibits the growth of DU-145 cells with IC50 of 0.11 μM. HDAC42 is potent in suppressing the proliferation of U87MG and PC-3 cells, in part, because of its ability to down-regulate Akt signaling. AR-42 inhibits the growth of PC-3 and LNCaP cells with IC50 of 0.48 μM and 0.3 μM, respectively. Compared to SAHA, AR-42 exhibits distinctly superior apoptogenic potency, and causes markedly greater decreases in phospho-Akt, Bcl-xL, and survivin in PC-3 cells. AR-42 treatment induces growth inhibition, cell- cycle arrest, apoptosis, and activation of caspases-3/7 in malignant mast cell lines. AR-42 treatment induces down-regulation of Kit via inhibition of Kit transcription, disassociation between Kit and heat shock protein 90 (HSP90), and up-regulation of HSP70. AR-42 treatment down-regulates the expression of p-Akt, total Akt, phosphorylated STAT3/5 (pSTAT3/5), and total STAT3/5. AR-42 potently inhibits the growth of JeKo-1, Raji, and 697 cells with IC50 of <0.61 μM. AR-42 also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. AR-42 treatment also induces autophagy through downregulation of Akt/mTOR signaling and inducing ER stress in hepatocellular carcinoma (HCC) cells.體內(nèi)研究
The growth of PC-3 tumor xenografts is suppressed by 52% and 67% after treatment with AR-42 at 25 mg/kg and 50 mg/kg, respectively, whereas SAHA at 50 mg/kg suppresses growth by 31%. In contrast to mice treated with SAHA, intratumoral levels of phospho-Akt and Bcl-xL are markedly reduced in AR-42 treated mice. In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, administration of AR-42 not only decreases the severity of prostatic intraepithelial neoplasia (PIN) and completely prevents its progression to poorly differentiated carcinoma, but also shifts tumorigenesis to a more differentiated phenotype, suppressing absolute and relative urogenital tract weights by 86% and 85%, respectively. AR-42 significantly reduces leukocyte counts, and prolongs survival in three separate mouse models of B-cell malignancy without evidence of toxicity.特征
More potent than SAHA.生物活性
AR-42 (HDAC-42) 是一種HDAC抑制劑，IC50為30 nM。Phase 1。靶點(diǎn)
| Target | Value |
|
HDAC
(Cell-free assay) | 30 nM |
體外研究
AR-42治療誘導(dǎo)組蛋白高度乙?；蚿21 HDAC42能夠有效抑制U87MG和PC-3細(xì)胞的增殖，某種程度上是因?yàn)镠DAC42能夠下調(diào)Akt信號(hào)。 AR-42抑制PC-3和LNCaP細(xì)胞的生長(zhǎng)，IC50分別為0.48 μM 和0.3 μM。與SAHA相比，AR-42表現(xiàn)出顯著更高的促凋亡作用，并引起PC-3細(xì)胞中磷酸化-Akt，Bcl-xL，和存活素大大下降。 在惡性肥大細(xì)胞系中，AR-42治療誘導(dǎo)生長(zhǎng)抑制，細(xì)胞周期阻滯，細(xì)胞凋亡，和caspases-3/7的活化。AR-42治療通過(guò)抑制Kit轉(zhuǎn)錄和Kit與熱休克蛋白90 (HSP90)的解離而下調(diào)Kit，并上調(diào)HSP70。AR-42治療下調(diào)p-Akt，總Akt，磷酸化STAT3/5 (pSTAT3/5)，和總STAT3/5的表達(dá)。 AR-42有效抑制JeKo-1，Raji，和697細(xì)胞的生長(zhǎng)，IC50為<0.61 μM。AR-42也會(huì)使CLL細(xì)胞對(duì)TNF相關(guān)的凋亡誘導(dǎo)配體(TRAIL)敏感，可能是通過(guò)c-FLIP的減少發(fā)揮作用。 在肝腫瘤(HCC)細(xì)胞中，AR-42治療也會(huì)通過(guò)下調(diào)Akt/mTOR信號(hào)，并誘導(dǎo)ER壓力，從而誘導(dǎo)自我吞噬。
體內(nèi)研究
25 mg/kg和50 mg/kg 的AR-42處理后，PC-3腫瘤異種移植物的生長(zhǎng)分別被抑制52% 和67%，而50 mg/kg的SAHA僅抑制31%的生長(zhǎng)。與SAHA處理的小鼠相比，磷酸化-Akt和Bcl-xL的瘤內(nèi)水平在AR-42處理的小鼠體內(nèi)顯著下降。在轉(zhuǎn)基因腺癌的小鼠前列腺(TRAMP)模型中，AR-42給藥不僅降低前列腺上皮內(nèi)瘤(PIN)的嚴(yán)重度，并完全阻止低分化腫瘤的進(jìn)程，而且將腫瘤生成轉(zhuǎn)化為更多的分化表型，分別抑制86%和85%絕對(duì)的和相對(duì)的泌尿生殖道重量。 AR-42顯著降低白血球數(shù)，并且在三個(gè)負(fù)荷B細(xì)胞惡性腫瘤的獨(dú)立小鼠模型中，能夠延長(zhǎng)小鼠的生存時(shí)間，而沒有毒性。