Resminostat

Resminostat
Names
Preferred IUPAC name
(2E)-3-(1-{4-[(Dimethylamino)methyl]benzene-1-sulfonyl}-1H-pyrrol-3-yl)-N-hydroxyprop-2-enamide
Other names
RAS2410; Resminostat 4SC-201
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
UNII
  • InChI=1S/C16H19N3O4S/c1-18(2)11-13-3-6-15(7-4-13)24(22,23)19-10-9-14(12-19)5-8-16(20)17-21/h3-10,12,21H,11H2,1-2H3,(H,17,20)/b8-5+
    Key: FECGNJPYVFEKOD-VMPITWQZSA-N
  • InChI=1/C16H19N3O4S/c1-18(2)11-13-3-6-15(7-4-13)24(22,23)19-10-9-14(12-19)5-8-16(20)17-21/h3-10,12,21H,11H2,1-2H3,(H,17,20)/b8-5+
    Key: FECGNJPYVFEKOD-VMPITWQZBF
  • CN(C)CC1=CC=C(C=C1)S(=O)(=O)N2C=CC(=C2)/C=C/C(=O)NO
Properties
C16H19N3O4S
Molar mass 349.41 g·mol−1
Density 1.282 g/cm3
Pharmacology
L01XH07 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Resminostat (4SC-201 or RAS2410) is an orally bioavailable inhibitor of histone deacetylases (HDACs), of which inhibitors are antineoplastic agents.[1]

In 2011, the German drug maker 4SC was granted orphan drug designation for resminostat by the US FDA for the treatment of hepatocellular carcinoma (HCC).[2]

In 2016, the FDA granted IND for clinical tests in combination with sorafenib for HCC.[3] 4SC say "In several phase I and phase II trials, resminostat has already demonstrated very good safety and tolerability, alongside promising indications of efficacy."[3]

Clinical trials

Resminostat has undergone a phase I/II clinical trial for K-ras mutated advanced colorectal carcinoma.[4]

It has undergone a phase II clinical trial for relapsed or refractory Hodgkin's lymphoma.[5]

Mechanism

Resminostat restrains the phosphorylation of 4E-BP1 and p70S6k, indicating a disturbance with Akt signalling pathway. The treatment of resminostat leads to a drop of Bim and Bax protein level and Bcl-xL level.[6]

As with other HDAC inhibitors such as pracinostat, the inhibition of HDACs by resminostat results in an accumulation of highly acetylated histones, followed by an abduction of chromatin remodeling, inhibition of tumor suppressor genes transcription and cell division, and finally tumor cell apoptosis.

References

  1. ^ Tsilimigras, D. I.; Ntanasis-Stathopoulos, I.; Moris, D.; Spartalis, E.; Pawlik, T. M. (2018). "Histone deacetylase inhibitors in hepatocellular carcinoma: A therapeutic perspective". Surgical Oncology. 27 (4). Elsevier Surg Oncol 2018 Dec;27(4):611-618.doi: 10.1016/j.suronc.2018.07.015.Epub 2018 Jul 30.: 611–618. doi:10.1016/j.suronc.2018.07.015. PMID 30449480. S2CID 53947365.
  2. ^ "4SC's Anti-Cancer Drug Resminostat achieves Median Overall Survival of 8.0 Months in Second-Line Advanced Liver Cancer (HCC) Patients". September 2012.
  3. ^ a b 4SC AG: FDA approves IND application for resminostat in liver cancer. Feb 2016
  4. ^ 4SC-201 (Resminostat) in Advanced Colorectal Carcinoma (SHORE)
  5. ^ Resminostat (4SC-201) in Relapsed or Refractory Hodgkin's Lymphoma (SAPHIRE)
  6. ^ Brunetto AT, et al. (1 Oct 2013). "First-in-human, pharmacokinetic and pharmacodynamic phase I study of Resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors". Clin Cancer Res. 19 (19): 5494–504. doi:10.1158/1078-0432.CCR-13-0735. PMC 3790647. PMID 24065624.

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