RGFP966

RGFP966 is a selective inhibitor of HDAC3 with IC50 value of 80 nM [1].

HDAC3 (histone deacetylase 3) is an isoform of HDACs family and plays an important role in DNA transcriptional regulation. It has been shown that HDACs involves in a variety of biologic processes, like DNA repair, replication, transcription and chromatin structure. Many studies have shown that HDACs is the most highly expressed class I HDAC in the brain and involves in learning and memory process negatively [2].

RGFP966 is a potent HDAC3 inhibitor and has no inhibition on other HDACs at the concentration up to 15 μM. Using a substrate-dependent biochemical assay to investigate RGFP966 inhibition of HDACs, and results showed that it inhibited HDAC3 with IC50 value of 80 nM while had no effective inhibition on other HDACs [1]. When tested with cutaneous T cell lymphoma (CTCL) cell lines with RGFP966, the cell growth were significantly decreased by inhibiting HDAC3 which increased cell apoptosis [3].

In male C57BL/6J mice model, trained them in object recognition (ORM) and location-dependent object recognition (OLM) with a subthreshold period after administration of RGFP966 significantly increased the novel object preference and enhanced enhanced long-term OLM in a dose-dependent manner [1].

References:
[1].  Malvaez, M., et al., HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc Natl Acad Sci U S A, 2013. 110(7): p. 2647-52.
[2].  Rogge, G.A., et al., HDAC3 is a negative regulator of cocaine-context-associated memory formation. J Neurosci, 2013. 33(15): p. 6623-32.
[3].  Wells, C.E., et al., Inhibition of histone deacetylase 3 causes replication stress in cutaneous T cell lymphoma. PLoS One, 2013. 8(7): p. e68915.

HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-kappaB p65 transcriptional activity.[Pubmed:26993378]

Biochem Pharmacol. 2016 May 15;108:58-74.

The increasing number of patients suffering from chronic obstructive pulmonary disease (COPD) represents a major and increasing health problem. Therefore, novel therapeutic approaches are needed. Class I HDACs 1, 2 and 3 play key roles in the regulation of inflammatory gene expression with a particular pro-inflammatory role for HDAC 3. HDAC 3 has been reported to be an important player in inflammation by deacetylating NF-kappaB p65, which has been implicated in the pathology of COPD. Here, we applied the pharmacological HDAC 3-selective inhibitor RGFP966, which attenuated pro-inflammatory gene expression in models for inflammatory lung diseases. Consistent with this, a robust decrease of the transcriptional activity of NF-kappaB p65 was observed. HDAC 3 inhibition affected neither the acetylation status of NF-kappaB p65 nor histone H3 or histone H4. This indicates that HDAC 3 inhibition does not inhibit NF-kappaB p65 transcriptional activity by affecting its deacetylation but rather by inhibiting enzymatic activity of HDAC 3. Taken together, our findings indicate that pharmacological HDAC 3-selective inhibition by inhibitors such as RGFP966 may provide a novel and effective approach toward development of therapeutics for inflammatory lung diseases.

Histone Deacetylase Inhibition via RGFP966 Releases the Brakes on Sensory Cortical Plasticity and the Specificity of Memory Formation.[Pubmed:26400942]

J Neurosci. 2015 Sep 23;35(38):13124-32.

Research over the past decade indicates a novel role for epigenetic mechanisms in memory formation. Of particular interest is chromatin modification by histone deacetylases (HDACs), which, in general, negatively regulate transcription. HDAC deletion or inhibition facilitates transcription during memory consolidation and enhances long-lasting forms of synaptic plasticity and long-term memory. A key open question remains: How does blocking HDAC activity lead to memory enhancements? To address this question, we tested whether a normal function of HDACs is to gate information processing during memory formation. We used a class I HDAC inhibitor, RGFP966 (C21H19FN4O), to test the role of HDAC inhibition for information processing in an auditory memory model of learning-induced cortical plasticity. HDAC inhibition may act beyond memory enhancement per se to instead regulate information in ways that lead to encoding more vivid sensory details into memory. Indeed, we found that RGFP966 controls memory induction for acoustic details of sound-to-reward learning. Rats treated with RGFP966 while learning to associate sound with reward had stronger memory and additional information encoded into memory for highly specific features of sounds associated with reward. Moreover, behavioral effects occurred with unusually specific plasticity in primary auditory cortex (A1). Class I HDAC inhibition appears to engage A1 plasticity that enables additional acoustic features to become encoded in memory. Thus, epigenetic mechanisms act to regulate sensory cortical plasticity, which offers an information processing mechanism for gating what and how much is encoded to produce exceptionally persistent and vivid memories. Significance statement: Here we provide evidence of an epigenetic mechanism for information processing. The study reveals that a class I HDAC inhibitor (Malvaez et al., 2013; Rumbaugh et al., 2015; RGFP966, chemical formula C21H19FN4O) alters the formation of auditory memory by enabling more acoustic information to become encoded into memory. Moreover, RGFP966 appears to affect cortical plasticity: the primary auditory cortex reorganized in a manner that was unusually "tuned-in" to the specific sound cues and acoustic features that were related to reward and subsequently remembered. We propose that HDACs control "informational capture" at a systems level for what and how much information is encoded by gating sensory cortical plasticity that underlies the sensory richness of newly formed memories.

RGFP966 is a highly selective HDAC3 inhibitor with an IC50 of 80 nM and shows no inhibition to other HDACs at concentrations up to 15 μM.

RGFP966,1357389-11-7,1396841-57-8,Natural Products,HDAC, buy RGFP966 , RGFP966 supplier , purchase RGFP966 , RGFP966 cost , RGFP966 manufacturer , order RGFP966 , high purity RGFP966