Pharmacological Properties and Clinical Application Research Progress of Entinostat
1. Basic Information and Molecular Characteristics of the Drug
Entinostat, developed under the code MS-275 or SNDX-275, is a selective histone deacetylase (HDAC) inhibitor with significant clinical value. This compound was first synthesized in 1999 by Japanese scientists, with its chemical name being N-(2-amino phenyl)-4-[N-(pyridine-3-carbonyl) aminomethyl] benzamide, and CAS registration number 209783-80-2. In terms of molecular structure, entinostat has a molecular formula of C21H20N4O3 and a molecular weight of 376.41, belonging to the class of benzamide HDAC inhibitors.
In terms of physicochemical properties, entinostat appears as a white to off-white solid powder at room temperature. Recommended storage conditions are: solid powder can be stably stored at -20°C for three years; if prepared in solution form, it needs to be stored at -80°C for two years or at -20°C for one year. These special storage requirements relate to the active amino groups and amide groups contained within its molecular structure that may undergo slow hydrolysis reactions when in solution.
2. Mechanism of Action and Target Selectivity
As a second-generation HDAC inhibitor, entinostat's most notable feature is its highly selective inhibition against Class I HDAC subtypes. Specifically, in cell-free experimental systems, this compound exhibits half-maximal inhibitory concentrations (IC50) against HDAC1 and HDAC3 reaching 0.51μM and 1.7μM respectively—significantly higher than its effects on Class II HDAC subtypes such as HDAC4, HDAC6, HDAC8, and HDAC10. This selectivity arises from entinostat’s ability to precisely recognize specific amino acid residues within the catalytic pocket of Class I HDACs forming stable enzyme-inhibitor complexes.
From a molecular mechanism perspective analysis shows that entinostat increases intracellular histone acetylation levels by inhibiting HDAC activity which subsequently alters chromatin structure and gene expression profiles. This epigenetic regulation can simultaneously activate tumor suppressor genes while inhibiting oncogenes' expression levels notably upregulating cyclin-dependent protein p21Cip1/Waf1—a key event inducing tumor cell cycle arrest Furthermore this drug also modulates Bcl-2 family proteins’ balance activating caspase cascade reactions ultimately triggering apoptosis in tumor cells.
3.In Vitro Pharmacodynamics Studies
Numerous in vitro experimental data confirm that entinostat exhibits significant anti-proliferative activity across various hematologic malignancy cell lines including human leukemia & lymphoma cell lines (U937 HL-60 K562 Jurkat). At an administration concentration level around (1 μM), clear dose-dependent effects were observed where noticeable growth stagnation occurred alongside increased differentiation marker CD11b expressions After extending treatment duration up until (48 hours), approximately (70%)of malignant cells underwent programmed death processes .
Mechanistic studies reveal dual activation pathways involved during apoptosis induced via treatments namely mitochondrial pathway & death receptor pathway leading toward decreased mitochondrial membrane potentials cytochrome C releases followed by sequential activations involving caspases(caspase−9 caspase−3)simultaneously demonstrating marked elevations regarding Fas death receptors along with their ligands indicating participation throughout these apoptotic processes providing comprehensive insights into understanding anticancer mechanisms behind this medication .
Four: In Vivo Pharmacodynamics And Animal Model Studies nWithin multiple transplantable tumor animal models ,entinosat exhibited promising antitumor efficacy pharmacodynamic experiments indicated substantial suppression achieved through administering doses like(49 mg/kg )against KB −31 ST −4 tumors whilst moderate effectiveness noted concerning Caplan –I tumors Notably even lowering dosages down towards(24 .5mg/kg)(12 .3mg/kg ),entinosat still maintained considerable antitumor activities observed over timeframes evaluated through biological dynamics assessments confirming effective targeting capabilities evidenced via sustained elevations surrounding histone acetylation rates detected among HT −29 xenograft models post oral administrations ranging between four twenty-four hour intervals showcasing ideal bioavailability outcomes supporting potential clinical applications using intermittent dosing regimens closely linked together within therapeutic settings related herewith!
### Five :Clinical Research Advances And Prospects Based On robust preclinical evidence ,entinostats currently engaged several ongoing trials primarily focusing indications encompassing relapsed/refractory Hodgkin lymphomas non-small-cell lung cancers hormone receptor-positive breast cancer etc Initial results demonstrate encouraging safety profiles alongside impressive anticancer activities particularly when combined other epigenetic agents immune checkpoint inhibitors! From developmental perspectives representing novel targeted approaches combating traditional chemotherapeutic resistance challenges emerging strategies warrant exploration optimizing delivery methods synergizing combinations developing reliable biomarkers predicting efficacies maximizing benefits derived therapeutically! n ### Six :Supplier Information Resources Currently available suppliers offering research-grade compounds include SparkJade specializing small-molecule offerings exceeding twenty thousand distinct options covering eight hundred plus targets spanning critical signaling pathways applicable areas oncology neurodegenerative disorders cardiovascular diseases enabling researchers tailor selections based upon experimentation requirements while emphasizing products strictly designated scientific inquiries prohibiting usage relating human/animal clinical interventions.