A Structure-based Design Approach for Generating High Affinity BRD4 D1-Selective Chemical Probes

2022 ◽  
Author(s):  
Huarui Cui ◽  
Anand Divakaran ◽  
Zachariah J. Hoell ◽  
Mikael O. Ellingson ◽  
Cole R. Scholtz ◽  
...  
Keyword(s):  
Design Approach ◽  
Chemical Probes ◽  
High Affinity ◽  
Selective Chemical

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

2021 ◽  
Author(s):  
Raphael R. Steimbach ◽  
Corey J. Herbst-Gervasoni ◽  
Glynis Klinke ◽  
Magalie Géraldy ◽  
Gergely Tihanyi ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Target Engagement ◽  
Target Validation ◽  
Chemical Probes ◽  
Combination Cancer Therapy ◽  
Selective Chemical ◽  
First Time ◽  
Double Digit ◽  
Novel Therapeutic ◽  
Thermal Shift

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.

scholarly journals Development and Optimization of Piperidyl-1,2,3-Triazole Ureas as Selective Chemical Probes of Endocannabinoid Biosynthesis

2013 ◽  
Vol 56 (21) ◽  
pp. 8257-8269 ◽  
Author(s):  
Ku-Lung Hsu ◽  
Katsunori Tsuboi ◽  
Landon R. Whitby ◽  
Anna E. Speers ◽  
Holly Pugh ◽  
...  
Keyword(s):  
Chemical Probes ◽  
Selective Chemical

Cyanobacterial Peptides as a Prototype for the Design of Potent β-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases

2012 ◽  
Vol 55 (23) ◽  
pp. 10749-10765 ◽  
Author(s):  
Yanxia Liu ◽  
Wei Zhang ◽  
Li Li ◽  
Lilibeth A. Salvador ◽  
Tiantian Chen ◽  
...  
Keyword(s):  
Chemical Probes ◽  
Aspartic Proteases ◽  
Selective Chemical

Terpyridine-based complex nanofibers with Eu3+ as a highly selective chemical probes for UO22+

2019 ◽  
Vol 378 ◽  
pp. 120713 ◽  
Author(s):  
Seonae Lee ◽  
Ka Young Kim ◽  
Na Young Lim ◽  
Jin Hwan Jung ◽  
Ji Ha Lee ◽  
...  
Keyword(s):  
Chemical Probes ◽  
Selective Chemical

scholarly journals Downfalls of Chemical Probes Acting at the Kinase ATP-Site: CK2 as a Case Study

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1977
Author(s):  
Eleanor L. Atkinson ◽  
Jessica Iegre ◽  
Paul D. Brear ◽  
Elizabeth A. Zhabina ◽  
Marko Hyvönen ◽  
...  
Keyword(s):  
Protein Kinases ◽  
The Novel ◽  
Chemical Probes ◽  
Alternative Strategies ◽  
Competitive Inhibitors ◽  
Coronavirus Infection ◽  
Selective Chemical ◽  
Novel Coronavirus ◽  
Kinase Ck2

Protein kinases are a large class of enzymes with numerous biological roles and many have been implicated in a vast array of diseases, including cancer and the novel coronavirus infection COVID-19. Thus, the development of chemical probes to selectively target each kinase is of great interest. Inhibition of protein kinases with ATP-competitive inhibitors has historically been the most widely used method. However, due to the highly conserved structures of ATP-sites, the identification of truly selective chemical probes is challenging. In this review, we use the Ser/Thr kinase CK2 as an example to highlight the historical challenges in effective and selective chemical probe development, alongside recent advances in the field and alternative strategies aiming to overcome these problems. The methods utilised for CK2 can be applied to an array of protein kinases to aid in the discovery of chemical probes to further understand each kinase’s biology, with wide-reaching implications for drug development.

scholarly journals First-generation species-selective chemical probes for fluorescence imaging of human senescence-associated β-galactosidase

2020 ◽  
Vol 11 (28) ◽  
pp. 7292-7301 ◽  
Author(s):  
Xiaokang Li ◽  
Wenjing Qiu ◽  
Jinwen Li ◽  
Xi Chen ◽  
Yulu Hu ◽  
...  
Keyword(s):  
Fluorescence Imaging ◽  
First Generation ◽  
Chemical Probes ◽  
Selective Chemical

The first-generation chemical probes for species-selective fluorescence imaging of human senescence-associated β-galactosidase are developed.

scholarly journals Histone Deacetylase 11 is an ε-N-Myristoyllysine Hydrolase

2017 ◽  
Author(s):  
Carlos Moreno-Yruela ◽  
Iacopo Galleano ◽  
Andreas S. Madsen ◽  
Christian A. Olsen
Keyword(s):  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Biological Function ◽  
Hdac Inhibitors ◽  
The Other ◽  
Chemical Probes ◽  
Chain Acyl ◽  
Selective Chemical ◽  
Approved Drugs ◽  
Long Chain

SUMMARYHistone deacetylase (HDAC) enzymes are important regulators of diverse biological function, including gene expression, rendering them potential targets for intervention in a number of diseases, with a handful of compounds approved for treatment of certain hematologic cancers. Among the human zinc-dependent HDACs, the most recently discovered member, HDAC11, is the only member assigned to subclass IV, the smallest protein, and the least well understood with regards to biological function. Here we show that HDAC11 cleaves long chain acyl modifications on lysine side chains with remarkable efficiency compared to acetyl groups. We further show that several common types of HDAC inhibitors, including the approved drugs romidepsin and vorinostat, do not inhibit this enzymatic activity. Macrocyclic hydroxamic acid-containing peptides, on the other hand, potently inhibit HDAC11 demyristoylation activity. These findings should be taken carefully into consideration in future investigations of the biological function of HDAC11 and will serve as a foundation for the development of selective chemical probes targeting HDAC11.

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