935881-37-1

AR-42是一种HDAC抑制剂，IC50为30 nM。Phase 1。

AR-42 treatment induces histone hyperacetylation and p21^WAF/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.

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.

More potent than SAHA.

AR-42 (HDAC-42) 是一种HDAC抑制剂，IC50为30 nM。Phase 1。

Target	Value
HDAC (Cell-free assay)	30 nM

AR-42治疗诱导组蛋白高度乙酰化和p21 HDAC42能够有效抑制U87MG和PC-3细胞的增殖，某种程度上是因为HDAC42能够下调Akt信号。 AR-42抑制PC-3和LNCaP细胞的生长，IC50分别为0.48 μM 和0.3 μM。与SAHA相比，AR-42表现出显著更高的促凋亡作用，并引起PC-3细胞中磷酸化-Akt，Bcl-xL，和存活素大大下降。 在恶性肥大细胞系中，AR-42治疗诱导生长抑制，细胞周期阻滞，细胞凋亡，和caspases-3/7的活化。AR-42治疗通过抑制Kit转录和Kit与热休克蛋白90 (HSP90)的解离而下调Kit，并上调HSP70。AR-42治疗下调p-Akt，总Akt，磷酸化STAT3/5 (pSTAT3/5)，和总STAT3/5的表达。 AR-42有效抑制JeKo-1，Raji，和697细胞的生长，IC50为<0.61 μM。AR-42也会使CLL细胞对TNF相关的凋亡诱导配体(TRAIL)敏感，可能是通过c-FLIP的减少发挥作用。 在肝肿瘤(HCC)细胞中，AR-42治疗也会通过下调Akt/mTOR信号，并诱导ER压力，从而诱导自我吞噬。

25 mg/kg和50 mg/kg 的AR-42处理后，PC-3肿瘤异种移植物的生长分别被抑制52% 和67%，而50 mg/kg的SAHA仅抑制31%的生长。与SAHA处理的小鼠相比，磷酸化-Akt和Bcl-xL的瘤内水平在AR-42处理的小鼠体内显著下降。在转基因腺癌的小鼠前列腺(TRAMP)模型中，AR-42给药不仅降低前列腺上皮内瘤(PIN)的严重度，并完全阻止低分化肿瘤的进程，而且将肿瘤生成转化为更多的分化表型，分别抑制86%和85%绝对的和相对的泌尿生殖道重量。 AR-42显著降低白血球数，并且在三个负荷B细胞恶性肿瘤的独立小鼠模型中，能够延长小鼠的生存时间，而没有毒性。