Rational Design and Synthesis of Enzyme Inhibitors: Significance in Probing the Function of Enzymes

ChemInform ◽  
2003 ◽  
Vol 34 (15) ◽  
Author(s):  
Jun Hiratake
Keyword(s):  
Rational Design ◽  
Enzyme Inhibitors ◽  
Design And Synthesis

scholarly journals Structure-Based Design of a Macrocyclic PROTAC

2019 ◽  
Author(s):  
Andrea Testa ◽  
Scott J. Hughes ◽  
Xavier Lucas ◽  
Jane E. Wright ◽  
Alessio Ciulli
Keyword(s):  
Crystal Structure ◽  
Rational Design ◽  
Ternary Complex ◽  
Enzyme Inhibitors ◽  
Cellular Activity ◽  
Chemical Probes ◽  
Bioactive Conformation ◽  
Bifunctional Molecules ◽  
Design And Synthesis ◽  
Biophysical Studies

Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Here, we report the design and synthesis of a first macrocyclic PROTAC by adding a second cyclizing linker to the BET degrader MZ1. A co-crystal structure of macroPROTAC-1 bound in a ternary complex with VHL and the second Brd4 bromodomain validated the rational design. Biophysical studies revealed enhanced discrimination between the second and the first bromodomains of BET proteins. Despite a 12-fold loss of binary binding affinity for Brd4, macroPROTAC-1 exhibited cellular activity comparable to MZ1. Our findings support macrocyclization as an advantageous strategy to enhance PROTAC degradation potency and selectivity between homologous targets.

scholarly journals Structure-Based Design of a Macrocyclic PROTAC

2019 ◽  
Author(s):  
Andrea Testa ◽  
Scott J. Hughes ◽  
Xavier Lucas ◽  
Jane E. Wright ◽  
Alessio Ciulli
Keyword(s):  
Crystal Structure ◽  
Rational Design ◽  
Ternary Complex ◽  
Enzyme Inhibitors ◽  
Cellular Activity ◽  
Chemical Probes ◽  
Bioactive Conformation ◽  
Bifunctional Molecules ◽  
Design And Synthesis ◽  
Biophysical Studies

Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Here, we report the design and synthesis of a first macrocyclic PROTAC by adding a second cyclizing linker to the BET degrader MZ1. A co-crystal structure of macroPROTAC-1 bound in a ternary complex with VHL and the second Brd4 bromodomain validated the rational design. Biophysical studies revealed enhanced discrimination between the second and the first bromodomains of BET proteins. Despite a 12-fold loss of binary binding affinity for Brd4, macroPROTAC-1 exhibited cellular activity comparable to MZ1. Our findings support macrocyclization as an advantageous strategy to enhance PROTAC degradation potency and selectivity between homologous targets.

scholarly journals Structure-Based Design of a Macrocyclic PROTAC

2019 ◽  
Author(s):  
Andrea Testa ◽  
Scott J. Hughes ◽  
Xavier Lucas ◽  
Jane E. Wright ◽  
Alessio Ciulli
Keyword(s):  
Crystal Structure ◽  
Rational Design ◽  
Enzyme Inhibitors ◽  
Protein Complexes ◽  
Linear Molecule ◽  
Chemical Probes ◽  
Bifunctional Molecules ◽  
Design And Synthesis ◽  
Biophysical Studies ◽  
New Interactions

Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to design enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Here, we report the design and synthesis of a first macrocyclic PROTAC based on co-crystal structure of a parent linear molecule, by adding a cyclizing linker. A co-crystal structure of the macrocyclic PROTAC bound in a ternary complex with VHL and Brd4 validated the rational design and identified new interactions formed by the new linker. Biophysical studies revealed that the macrocycle selectively discriminated the second against the first bromodomains of BET proteins, and is a potent Brd4 degrader. Macrocyclization provides a viable strategy to induce protein-protein complexes and protein degradation inside cells.

scholarly journals Rational Design and Synthesis of Right-Handed d-Sulfono-γ-AApeptide Helical Foldamers as Potent Inhibitors of Protein–Protein Interactions

2020 ◽  
Vol 85 (16) ◽  
pp. 10552-10560
Author(s):  
Peng Sang ◽  
Yan Shi ◽  
Pirada Higbee ◽  
Minghui Wang ◽  
Sami Abdulkadir ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Rational Design ◽  
Protein Protein Interactions ◽  
Design And Synthesis

Rational design and synthesis of novel Syk-kinase inhibitors

2012 ◽  
Vol 22 (2) ◽  
pp. 73-74 ◽  
Author(s):  
Alexey A. Zeifman ◽  
Ilya Yu. Titov ◽  
Igor V. Svitanko ◽  
Tatiana V. Rakitina ◽  
Aleksey V. Lipkin ◽  
...  
Keyword(s):  
Rational Design ◽  
Kinase Inhibitors ◽  
Design And Synthesis ◽  
Syk Kinase

Rational design and synthesis of multimorphology mesoporous carbon@silica nanoparticles with tailored structure

Carbon ◽  
2021 ◽  
Author(s):  
Yajuan Zhao ◽  
Haolin Lyu ◽  
Yujie Liu ◽  
Wenjie Liu ◽  
Yong Tian ◽  
...  
Keyword(s):  
Silica Nanoparticles ◽  
Mesoporous Carbon ◽  
Rational Design ◽  
Design And Synthesis

scholarly journals Rational Design and Synthesis of a Novel Anti-leukemic Agent Targeting Bruton′s Tyrosine Kinase (BTK), LFM-A13 [α-Cyano-β-Hydroxy-β-Methyl-N-(2,5-Dibromophenyl)Propenamide]

1999 ◽  
Vol 274 (14) ◽  
pp. 9587-9599 ◽  
Author(s):  
Sandeep Mahajan ◽  
Sutapa Ghosh ◽  
Elise A. Sudbeck ◽  
Yaguo Zheng ◽  
Suzanne Downs ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Rational Design ◽  
Design And Synthesis
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