Exploring the pharmacokinetic properties of phosphorus-containing selective HDAC 1 and 2 inhibitors (SHI-1:2)

Heidebrecht, Richard W.; Chénard, Mélissa; Close, Joshua; Dahlberg, William K.; Fleming, James E.; Grimm, Jonathan B.; Hamill, Julie E.; Harsch, Andreas; Haines, Brian B.; Hughes, Bethany; Kral, Astrid M.; Middleton, Richard E.; Mushti, Chandrasekhar; Ozerova, Nicole; Szewczak, Alexander A.; Wang, Hongmei; Wilson, Kevin; Witter, David J.; Secrist, J. Paul; Miller, Thomas A.

doi:10.1016/j.bmcl.2009.02.009

Cited by 19 publications

(11 citation statements)

References 23 publications

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“…This resulted in compounds such as 1 and 60 ( FiguRe 6) with aryl substituents that led to dramatic improvements in potency and selectivity for HDACs 1 and 2 versus all other HDACs. This watershed strategy described by Moradei et al was further exploited by researchers at Merck and Co. examining a large array of substituents that projected into the 14 Å internal cavity to better understand the nature of this structural motif and its relationship to Class I selectivity [46][47][48]. Their work highlighted a key residue difference between HDACs 1, 2 and 3, Ser113 (HDACs 1 and 2) → Tyr-96 (HDAC3), in the 14 Å internal cavity rationalizing the HDACs 1 and 2 selectivity [46].…”

Section: Development Of Hdac2 Selective Inhibitorsmentioning

confidence: 96%

Therapeutic Potential of Isoform Selective Hdac Inhibitors for the Treatment of Schizophrenia

et al. 2013

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Increasing evidence supports a role for epigenetic involvement in some of the neurobiological alterations observed in neurodegenerative and psychiatric disorders including schizophrenia. In particular, there is mounting evidence implicating dysfunction in acetylation status, a chromatin modification mediated in part by HDACs, as a possible contributing factor to certain facets of this debilitating disease. Additional data support the notion that small molecule inhibition of HDACs may provide therapeutic alternatives to treating many of the symptoms associated with schizophrenia, particularly cognitive deficits. However, the development of highly potent and selective inhibitors of the individual HDAC isoforms will be necessary to delineate the associated biological effects and test the feasibility of such an approach for this complex and chronically treated disease. Here, we summarize current evidence for the role of HDAC isoforms in schizophrenia and highlight the state of the art in developing selective inhibitors of these isoforms as a potential treatment for schizophrenia.

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Section: Development Of Hdac2 Selective Inhibitorsmentioning

confidence: 96%

Therapeutic Potential of Isoform Selective Hdac Inhibitors for the Treatment of Schizophrenia

et al. 2013

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“…Similarly, Heidebrecht et alreplaced the 3-pyridyl carbamate of 43 with a diethylphosphonate (45). This compound 45 was potent and selective for HDAC1 and HDAC2 (IC 50 8 nM) over HDAC3 (IC 50 12 M), HDAC4-HDAC11 (IC 50 >50 M) [109].…”

Section: Zinc-binding Groupsmentioning

confidence: 97%

Towards Isozyme-Selective HDAC Inhibitors For Interrogating Disease

Gupta¹,

Reid²,

Iyer³

et al. 2012

CTMC

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Histone deacetylase (HDAC) enzymes have emerged as promising targets for the treatment of a wide range of human diseases, including cancers, inflammatory and metabolic disorders, immunological, cardiovascular, and infectious diseases. At present, such applications are limited by the lack of selective inhibitors available for each of the eighteen HDAC enzymes, with most currently available HDAC inhibitors having broad-spectrum activity against multiple HDAC enzymes. Such broad-spectrum activity maybe useful in treating some diseases like cancers, but can be detrimental due to cytotoxic side effects that accompany prolonged treatment of chronic diseased states. Here we summarize progress towards the design and discovery of HDAC inhibitors that are selective for some of the eleven zinc-containing classical HDAC enzymes, and identify opportunities to use such isozyme-selective inhibitors as chemical probes for interrogating the biological roles of individual HDAC enzymes in diseases.

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“…Compound 20 (aka Compound 60 or Merck 60), an analog of CI-994 with an identical modification, is equally as potent and selective (IC 50 40 nM and 100 nM, 200-500-fold selective). This crucial and transformative discovery from Moradei et al [84] has been widely used to impart selectivity within the class I HDACs utilizing an array of substituents projecting into the 14 Å internal cavity [85][86][87]. The binding of these types of ligands into this internal cavity was confirmed by Takeda's published human HDAC2 crystal structure in complex with N -(4-aminobiphenyl-3-yl)benzamide (compound 1, Fig.…”

Section: Hdac1 2 and Hdac2 3 Selective Ortho-aminoanilide Inhibitorsmentioning

confidence: 53%

Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases

et al. 2013

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Lysine acetylation is an ancient, evolutionarily conserved, reversible post-translational modification. A multitude of diverse cellular functions are regulated by this dynamic modification, including energy and metabolism, protein folding, transcription, and translation. Gene expression can be manipulated through changes in histone acetylation status, and this process is controlled by the function of 2 opposing enzymes: histone acetyl transferases and histone deacetylases (HDACs). The zinc-dependent HDACs are a family of hydrolases that remove acetyl groups from lysines, and their function can be modulated by the action of small molecule ligands. Inhibition through competitive binding of the catalytic domain of these enzymes has been achieved by a diverse array of small molecule chemotypes. Structural biology has aided the development of potent, and in some cases highly isoformselective, inhibitors that have demonstrated utility in a number of neurological disease models. Continued development and characterization of highly optimized small molecule inhibitors of HDAC enzymes will help refine our understanding of their function and, optimistically, lead to novel therapeutic treatment alternatives for a host of neurological disorders.

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Exploring the pharmacokinetic properties of phosphorus-containing selective HDAC 1 and 2 inhibitors (SHI-1:2)

Cited by 19 publications

References 23 publications

Therapeutic Potential of Isoform Selective Hdac Inhibitors for the Treatment of Schizophrenia

Therapeutic Potential of Isoform Selective Hdac Inhibitors for the Treatment of Schizophrenia

Towards Isozyme-Selective HDAC Inhibitors For Interrogating Disease

Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases

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