scholarly journals Identification and Structure–Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors

2018 ◽  
Vol 61 (10) ◽  
pp. 4517-4527 ◽  
Author(s):  
Renato Ferreira de Freitas ◽  
Rachel J. Harding ◽  
Ivan Franzoni ◽  
Mani Ravichandran ◽  
Mandeep K. Mann ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Structure Activity Relationship ◽  
Binding Domain ◽  
Activity Relationship ◽  
Structure Activity ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Relationship Of

scholarly journals Identification and Structure-Activity Relationship of HDAC6 Zinc-finger Ubiquitin Binding Domain Inhibitors

2018 ◽  
Author(s):  
Renato Ferreira de Freitas ◽  
Rachel J. Harding ◽  
Ivan Franzoni ◽  
Mani Ravichandran ◽  
Mandeep K. Mann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Zinc Finger ◽  
Proteasome Inhibitors ◽  
Binding Pocket ◽  
Structure Activity Relationship ◽  
Binding Domain ◽  
Activity Relationship ◽  
Structure Activity ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

AbstractHDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation, and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of a HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155 are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens-up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.

scholarly journals Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain

2019 ◽  
Author(s):  
Mandeep K. Mann ◽  
Ivan Franzoni ◽  
Renato Ferreira de Freitas ◽  
Wolfram Tempel ◽  
Scott Houliston ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Allosteric Modulation ◽  
Binding Domain ◽  
Signalling Pathways ◽  
Chemical Library ◽  
Polyubiquitin Chains ◽  
Structure Activity ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Health And Disease

AbstractUSP5 disassembles unanchored polyubiquitin chains to recycle free mono-ubiquitin, and is one of twelve ubiquitin-specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a chemical library focused on the ZnF-UBD of USP5, crystallized hits in complex with the protein, and generated a preliminary structure-activity relationship which enables the development of more potent and selective compounds. This work serves as a framework for the discovery of a chemical probe to delineate the function of USP5 ZnF-UBD in proteasomal degradation and other ubiquitin signalling pathways in health and disease.

scholarly journals Structure Activity Relationship of USP5 Allosteric Inhibitors

2021 ◽  
Author(s):  
Mandeep K Mann ◽  
Carlos A Zepeda-Velazquez ◽  
Hector G Alvarez ◽  
Aiping Dong ◽  
Taira Kiyota ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Chemical Probe ◽  
Structural Framework ◽  
Structure Activity ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Multiple Ligands

USP5 is a deubiquitinase that has been implicated in a range of diseases, including cancer, but no USP5-targeting chemical probe has been reported to date. Here, we present the progression of a chemical series that occupies the C-terminal ubiquitin-binding site of a poorly characterized zinc-finger ubiquitin binding domain (ZnF-UBD) of USP5 and allosterically inhibits the catalytic activity of the enzyme. Systematic exploration of the structure-activity relationship, complemented with crystallographic characterization of the ZnF-UBD bound to multiple ligands, led to the identification of 64, which binds to the USP5 ZnF-UBD with a KD of 2.8 μM. 64 is selective over the structurally similar ZnF-UBD domain of HDAC6 and inhibits USP5 catalytic activity in vitro with an IC50 of 26 μM. This study provides a chemical and structural framework for the discovery of a chemical probe to delineate USP5 function in cells.

Structure-activity relationship of (-) mammea A/BB derivatives against Leishmania amazonensis

Planta Medica ◽  
2008 ◽  
Vol 74 (09) ◽  
Author(s):  
MA Brenzan ◽  
CV Nakamura ◽  
BPD Filho ◽  
T Ueda-Nakamura ◽  
MCM Young ◽  
...  
Keyword(s):  
Structure Activity Relationship ◽  
Leishmania Amazonensis ◽  
Activity Relationship ◽  
Structure Activity ◽  
Relationship Of

Antineoplastic Activity, Structural Modification, Synthesis and Structure-activity Relationship of Dammarane-type Ginsenosides: An Overview

2019 ◽  
Vol 23 (5) ◽  
pp. 503-516 ◽  
Author(s):  
Qiang Zhang ◽  
Xude Wang ◽  
Liyan Lv ◽  
Guangyue Su ◽  
Yuqing Zhao
Keyword(s):  
Structural Modification ◽  
Gastrointestinal Disease ◽  
Structure Activity Relationship ◽  
Cerebrovascular Diseases ◽  
Activity Relationship ◽  
Cycle Arrest ◽  
Structure Activity ◽  
Wide Range ◽  
Structural Association ◽  
Relationship Of

Dammarane-type ginsenosides are a class of tetracyclic triterpenoids with the same dammarane skeleton. These compounds have a wide range of pharmaceutical applications for neoplasms, diabetes mellitus and other metabolic syndromes, hyperlipidemia, cardiovascular and cerebrovascular diseases, aging, neurodegenerative disease, bone disease, liver disease, kidney disease, gastrointestinal disease and other conditions. In order to develop new antineoplastic drugs, it is necessary to improve the bioactivity, solubility and bioavailability, and illuminate the mechanism of action of these compounds. A large number of ginsenosides and their derivatives have been separated from certain herbs or synthesized, and tested in various experiments, such as anti-proliferation, induction of apoptosis, cell cycle arrest and cancer-involved signaling pathways. In this review, we have summarized the progress in structural modification, shed light on the structure-activity relationship (SAR), and offered insights into biosynthesis-structural association. This review is expected to provide a preliminary guide for the modification and synthesis of ginsenosides.

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