A novel HDAC inhibitor with a hydroxy-pyrimidine scaffold

Kemp, Melissa M.; Wang, Qiu; Fuller, Jason H.; West, Nathan; Martínez, Nicole M.; Morse, Elizabeth M.; Weïwer, Michel; Schreiber, Stuart L.; Bradner, James E.; Koehler, Angela N.

doi:10.1016/j.bmcl.2011.05.098

Cited by 18 publications

(7 citation statements)

References 33 publications

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“…This demonstrates that small structural changes in the zinc binding group greatly influence HDAC isoenzyme selectivity. In addition, several studies report the application of novel zinc binding groups including hydroxypyrimidine derivatives [ 65 ], ( R )-α-amino-ketones [ 66 ], 3-hydroxypyridin-2-thione derivatives [ 67 ], N -(5-ethyl-1,3,4-thiadiazol-2-yl)sulfonamides, and N -thiazol-2-yl sulfonamides [ 68 ] ( Figure 3 ). Further development of these scaffolds might provide HDAC inhibitors with completely new isoenzyme selectivities.…”

Section: Resultsmentioning

confidence: 99%

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

Cao

Zwinderman

2018

Molecules

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Histone deacetylases (HDACs) are epigenetic drug targets that have gained major scientific attention. Inhibition of these important regulatory enzymes is used to treat cancer, and has the potential to treat a host of other diseases. However, currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Several studies have shown that HDAC3, in particular, plays an important role in inflammation and degenerative neurological diseases, but the development of selective HDAC3 inhibitors has been challenging. This review provides an up-to-date overview of selective HDAC3 inhibitors, and aims to support the development of novel HDAC3 inhibitors in the future.

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Section: Resultsmentioning

confidence: 99%

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

Cao

Zwinderman

2018

Molecules

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“…Intrinsically disordered proteins (IDP) are now recognized in many diseases as critical etiologic proteins and the biochemical properties of these proteins actually supports their being targeted by small molecules [25–27]. The small molecules that target the IDP are generally lower affinity for their target than enzyme inhibitors [18, 28–30].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic modeling optimizes inhibition of the ‘undruggable’ EWS-FLI1 transcription factor in Ewing Sarcoma

et al. 2013

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Transcription factors have long been deemed ‘undruggable’ targets for therapeutics. Enhanced recognition of protein biochemistry as well as the need to have more targeted approaches to treat cancer has rendered transcription factors approachable for therapeutic development. Since transcription factors lack enzymatic domains, the specific targeting of these proteins has unique challenges. One challenge is the hydrophobic microenvironment that affects small molecules gaining access to block protein interactions. The most attractive transcription factors to target are those formed from tumor specific chromosomal translocations that are validated oncogenic driver proteins. EWS-FLI1 is a fusion protein that results from the pathognomonic translocation of Ewing sarcoma (ES). Our past work created the small molecule YK-4-279 that blocks EWS-FLI1 from interacting with RNA Helicase A (RHA). To fulfill long-standing promise in the field by creating a clinically useful drug, steps are required to allow for in vivo administration. These investigations identify the need for continuous presence of the small molecule protein-protein inhibitor for a period of days. We describe the pharmacokinetics of YK-4-279 and its individual enantiomers. In vivo studies confirm prior in vitro experiments showing (S)-YK-4-279 as the EWS-FLI1 specific enantiomer demonstrating both induction of apoptosis and reduction of EWS-FLI1 regulated caveolin-1 protein. We have created the first rat xenograft model of ES, treated with (S)-YK-4-279 dosing based upon PK modeling leading to a sustained complete response in 2 of 6 ES tumors. Combining laboratory studies, pharmacokinetic measurements, and modeling has allowed us to create a paradigm that can be optimized for in vivo systems using both in vitro data and pharmacokinetic simulations. Thus, (S)-YK-4-279 as a small molecule drug is ready for continued development towards a first-in-human, first-in-class, clinical trial.

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“…Hydroxypyrimidines ( 21 ) without contribution to the selectivity of HDACs were discovered to be a new ZBG 64 . The hydroxyl group and the pyrimidine group in the ZBG are both critical for activity, as revealed by SAR studies.…”

Section: Novel Zbgsmentioning

confidence: 99%

Zinc binding groups for histone deacetylase inhibitors

Zhang

Jiang

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

178

119

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Zinc binding groups (ZBGs) play a crucial role in targeting histone deacetylase inhibitors (HDACIs) to the active site of histone deacetylases (HDACs), thus determining the potency of HDACIs. Due to the high affinity to the zinc ion, hydroxamic acid is the most commonly used ZBG in the structure of HDACs. An alternative ZBG is benzamide group, which features excellent inhibitory selectivity for class I HDACs. Various ZBGs have been designed and tested to improve the activity and selectivity of HDACIs, and to overcome the pharmacokinetic limitations of current HDACIs. Herein, different kinds of ZBGs are reviewed and their features have been discussed for further design of HDACIs.

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A novel HDAC inhibitor with a hydroxy-pyrimidine scaffold

Cited by 18 publications

References 33 publications

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

Pharmacokinetic modeling optimizes inhibition of the ‘undruggable’ EWS-FLI1 transcription factor in Ewing Sarcoma

Zinc binding groups for histone deacetylase inhibitors

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