4SC-202

Domatinostat tosylate (4SC-202) is a selective class I HDAC inhibitor with IC50 of 1.20 μM, 1.12 μM, and 0.57 μM for HDAC1, HDAC2, and HDAC3, respectively. It also displays inhibitory activity against Lysine specific demethylase 1 (LSD1).

Research Areas >> Cancer

HDAC-3:0.57 μM (IC50)

HDAC-2:1.12 μM (IC50)

HDAC-1:1.2 μM (IC50)

HDAC-11:9.7 μM (IC50)

HDAC-5:11.3 μM (IC50)

HDAC-10:21 μM (IC50)

HDAC-9:50 μM (IC50)

Domatinostat tosylate significantly reduces proliferation of all epithelial and mesenchymal UC cell lines (IC50 0.15-0.51 μM), inhibits clonogenic growth and induces caspase activity[1]. Domatinostat tosylate provokes apoptosis activation in CRC cells, while caspase inhibitors (z-VAD-CHO and z-DVED-CHO) significantly alleviate Domatinostat tosylate-exerted cytotoxicity in CRC cells. Meanwhile, Domatinostat tosylate induces dramatic G2-M arrest in CRC cells. Further studies show that AKT activation might be an important resistance factor of Domatinostat tosylate. Domatinostat tosylate-induced cytotoxicity is dramatically potentiated with serum starvation, AKT inhibition (by perifosine or MK-2206), or AKT1-shRNA knockdown in CRC cells. On the other hand, exogenous expression of constitutively active AKT1 (CA-AKT1) decreases the sensitivity by Domatinostat tosylate in HT-29 cells. Notably, Domatinostat tosylate, at a low concentration, enhances oxaliplatin-induced in vitro anti-CRC activity[2]. Domatinostat tosylate treatment induces potent cytotoxic and proliferation-inhibitory activities against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Domatinostat tosylate induces apoptosis signal-regulating kinase 1 (ASK1) activation, causing it translocation to mitochondria and physical association with Cyp-D[3].

Oral gavage of Domatinostat tosylate inhibits HT-29 xenograft growth in nude mice, and when combined with oxaliplatin, its activity is further strengthened[2].

[1]. Pinkerneil M, et al. Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines. Target Oncol. 2016 Dec;11(6):783-798.

[2]. Zhijun H, et al. Pre-clinical characterization of 4SC-202, a novel class I HDAC inhibitor, against colorectal cancer cells. Tumour Biol. 2016 Aug;37(8):10257-67.

[3]. Fu M, et al. 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to inhibit hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2016 Mar 4;471(2):267-73

[4]. S.W.Henning, et al. Preclinical characterization of 4SC-202, a noval isotype specific HDAC inhibitor.

Trichostatin A | Entinostat (MS-275) | Romidepsin (FK228, Depsipeptide) | Mocetinostat(MGCD0103) | Ricolinostat (ACY-1215) | Sodium butyrate | RGFP 966 | Quisinostat | Tubacin | DL-Sulforaphane | CUDC-907 | LMK 235 | CI-994 | Tubastatin A | Sodium phenylbutyrate