Chemo-proteomics exploration of HDAC degradability by small molecule degraders

Xiong, Yuning; Donovan, Katherine A.; Eleuteri, Nicholas A.; Kirmani, Nadia; Yue, Hong; Razov, Anthony; Krupnick, Noah M.; Nowak, Radosław P.; Fischer, Eric S.

doi:10.1016/j.chembiol.2021.07.002

Cited by 60 publications

(77 citation statements)

References 84 publications

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“…That inhibition of HDAC10 enzymatic function is not cytotoxic, and does not sensitize neuroblastoma (BE(2)-C) cells toward drug treatment, suggests that a so far undescribed scaffolding or adaptor function of HDAC10 may exist. The development of selective HDAC10 degraders (41) and rescue experiments using mutant, enzymatically inactive HDAC10 could help to clarify these currently unanswered questions.…”

Section: Discussionmentioning

confidence: 99%

“…The highest gain in potency with retention of selectivity could be achieved by naphthamide cap groups in 39-42, while biphenyl 43 resulted in a loss of selectivity and potency despite the increased hydrophobic surface area. Among the naphtamides, DKFZ-748 (41) had the best HDAC10selectivity, superior over its regioisomer 42. We also probed the three aromatic substitution vectors of benzamide DKFZ-728 with aniline (44 and 45) and phenol functionalities (46 and 47), but no beneficial vector for additional H-bond donor/acceptors was identified.…”

Section: Sar Of the Capping Regionmentioning

confidence: 98%

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Aza-SAHA Derivatives are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation

Steimbach

Herbst-Gervasoni

Klinke

et al. 2021

Preprint

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We report the first selective chemical probes for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inserted an amino group (“aza-scan”) into the hexyl linker moiety of the approved drug Vorinostat (SAHA). This one atom replacement (C-->N) transformed SAHA from an unselective pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization of the aza-SAHA structure yielded DKFZ-748, which has a double-digit nanomolar IC50 against HDAC10 in cells and >500-fold selectivity over the closest relative HDAC6 as well as the Class I enzymes (HDAC1, 2, 3, 8). Potency of our aza-SAHA derivatives is rationalized with HDAC10 co-crystal structures and demonstrated by cellular and biochemical target-engagement, as well as thermal-shift, assays. Treatment of cells with DKFZ-748, followed by quantification of selected polyamines, confirmed for the first time the suspected cellular function of HDAC10 as a poly-amine deacetylase. Selective HDAC10 chemical probes provide a valuable pharmacological tool for target validation and will enable further studies on the enigmatic biology of HDAC10 and acetylated polyamines. HDAC10-selective aza-SAHA derivatives are not cytotoxic, which opens the doors to novel therapeutic applications as immunomodulators or in combination cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Sar Of the Capping Regionmentioning

confidence: 98%

Aza-SAHA Derivatives are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation

Steimbach

Herbst-Gervasoni

Klinke

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…When retaining both ends of the bifunctional molecule, while changing linker lengths, alterations in the selectivity profiles were noticed. These effects included loss of HDAC degradation activity in some cases [47].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity

Darwish

Ghazy

Heimburg

et al. 2022

Preprint

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While histone deacetylases (HDACs) are known as modulators of epigenetic gene regulation, they also control the activity of non-histone protein substrates. The isozyme HDAC8 plays a role in inhibiting apoptosis and increasing cancer cell proliferation. As a result, HDAC8 is considered a potential target in the treatment of cancer forms such as T-cell lymphoma, gastric adenocarcinoma, hepatocellular carcinoma, and childhood neuroblastoma. The present work describes the development of proteolysis targeting chimera (PROTAC) of HDAC8 based on substituted benzhydroxamic acids previously reported as potent and selective HDAC8 inhibitors. Within this study, we have developed the first in class HDAC8 selective PROTAC and investigated the effect on protein degradation and on the proliferation of neuroblastoma cells. The combination of structure-guided synthesis, in vitro screening and cellular testing resulted in cereblon (CRBN) based HDAC8 PROTACs that showed anti-neuroblastoma activity in cells.

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“…Using a library of pan-HDAC degraders, Xiong et al . investigated the degradability of zinc-dependent HDACs 54 . Together these broad-targeted degrader profiling experiments have greatly expanded the known degradable proteome.…”

Section: Introductionmentioning

confidence: 99%

“…Chemoproteomic profiling approaches have emerged as a systematic approach to survey protein degradability 50 . Rather than profiling expression of a single protein in response to a selective degrader, these approaches use mass spectrometry to assess the proteome-wide response to treatment with pan-targeting degraders [51][52][53][54] . For example, our recent study profiled 91 multikinase degraders to assess the degradability of more than 400 protein kinases, identifying more than 200 kinases as degradable 51 .…”

Section: Introductionmentioning

confidence: 99%

Machine learning modeling of protein-intrinsic features predicts tractability of targeted protein degradation

Zhang

Burman

Chen

et al. 2021

Preprint

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Targeted protein degradation (TPD) has rapidly emerged as a therapeutic modality to eliminate previously undruggable proteins by repurposing the cell's endogenous protein degradation machinery. However, the susceptibility of proteins for targeting by TPD approaches, termed "degradability", is largely unknown. Recent systematic studies to map the degradable kinome have shown differences in degradation between kinases with similar drug-target engagement, suggesting yet unknown factors influencing degradability. We therefore developed a machine learning model, MAPD (Model-based Analysis of Protein Degradability), to predict degradability from protein features that encompass post-translational modifications, protein stability, protein expression and protein-protein interactions. MAPD shows accurate performance in predicting kinases that are degradable by TPD compounds (auPRC=0.759) and is likely generalizable to independent non-kinase proteins. We found five features with statistical significance to achieve optimal prediction, with ubiquitination potential being the most predictive. By structural modeling, we found that E2-accessible ubiquitination sites, but not lysine residues in general, are particularly associated with kinase degradability. Finally, we extended MAPD predictions to the entire proteome to find 964 disease-causing proteins, including 278 cancer genes, that may be tractable to TPD drug development.

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Chemo-proteomics exploration of HDAC degradability by small molecule degraders

Abstract: Highlights d Pan-HDAC degrader library enabled chemo-proteomics map of HDAC degradability d HDAC degradation results in degradation of HDACcontaining repressive complexes d Cell line-dependent HDAC isoform specificity

Cited by 60 publications

References 84 publications

Aza-SAHA Derivatives are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation

Aza-SAHA Derivatives are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation

Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity

Machine learning modeling of protein-intrinsic features predicts tractability of targeted protein degradation

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