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.

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 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 Potent SIRT1 Enzyme-stimulating and Anti-glycation Activities of Polymethoxyflavonoids from Kaempferia parviflora

2014 ◽  
Vol 9 (9) ◽  
pp. 1934578X1400900 ◽  
Author(s):  
Asami Nakata ◽  
Yuka Koike ◽  
Hirofumi Matsui ◽  
Tsutomu Shimada ◽  
Masaki Aburada ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Kaempferia Parviflora ◽  
Structure Activity ◽  
Diabetes Drug ◽  
Sirt1 Activator

The SIRT1 enzyme-stimulating and anti-glycation activities of Kaempferia parviflora extract and its main polymethoxyflavonoids were evaluated in vitro. K. parviflora extract elevated SIRT1 catalytic activity by eight- and 17-fold at 20 μg/mL and 100 μg/mL, respectively, compared with vehicle only. Two major polymethoxyflavonoids, 3,5,7,3′,4′-pentamethoxyflavone (4) and 5,7,4′-trimethoxyflavone (5), were isolated from this extract and are four- and fivefold more potent than resveratrol, hitherto the strongest known natural SIRT1 activator. In addition, the anti-glycation activity of K. parviflora extract was observed to be seven times more effective than aminoguanidine, a clinical anti-diabetes drug. 3,5,7,3′,4′-Pentamethoxyflavone (4) and 5,7,4′-trimethoxyflavone (5) showed the strongest anti-glycation activity among the tested polymethoxyflavonoids. Further comparison of the activity of these structurally related polymethoxyflavonoids revealed a possible structure-activity relationship, in particular, for the contribution of methoxy moieties.

Recent Design and Structure-Activity Relationship Studies on Modifications of DHFR Inhibitors as Anticancer Agents

2019 ◽  
Vol 26 ◽  
Author(s):  
Agnieszka Wróbel ◽  
Danuta Drozdowska
Keyword(s):  
Anticancer Activity ◽  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Physicochemical Characterization ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Biological Research ◽  
Structure Activity ◽  
Dhfr Inhibitors

Background: Dihydrofolate reductase (DHFR) has been known for decades as a molecular target for antibacterial, antifungal and anti-malarial treatments. This enzyme is becoming increasingly important in the design of new anticancer drugs, which is confirmed by numerous studies including modelling, synthesis and in vitro biological research. This review aims to present and discuss some remarkable recent advances on the research of new DHFR inhibitors with potential anticancer activity. Methods: The scientific literature of the last decade on the different types of DHFR inhibitors has been searched. The studies on design, synthesis and investigation structure-activity relationship were summarized and divided into several subsections depending on the leading molecule and its structural modification. Various methods of synthesis, potential anticancer activity and possible practical applications as DHFR inhibitors of new chemical compounds were described and discussed. <p> Results: This review presents the current state of knowledge on the modification of known DHFR inhibitors and the structures and searching for over eighty new molecules, designed as potential anticancer drugs. In addition, DHFR inhibitors acting on thymidylate synthase (TS), carbon anhydrase (CA) and even DNA-binding are presented in this paper. <p> Conclusion: Thorough physicochemical characterization and biological investigations it is possible to understand structure-activity relationship of DHFR inhibitors. This will enable even better design and synthesis of active compounds, which would have the expected mechanism of action and the desired activity.

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