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Structure-activity relationship studies of SETD8 inhibitors
Anqi Ma1, Wenyu Yu2, Yan Xiong1
1Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States.
Medchemcomm
|January 3, 2015
Summary
Researchers explored novel SETD8 inhibitors, focusing on structure-activity relationships of quinazoline-based compounds. This led to new potent inhibitors targeting SETD8, a key enzyme in cellular processes.
Area of Science:
- Biochemistry
- Epigenetics
- Medicinal Chemistry
Background:
- SETD8 (lysine methyltransferase 5A) is the sole enzyme catalyzing histone H4 lysine 20 (H4K20) monomethylation.
- SETD8 also modifies non-histone proteins like p53 and PCNA, impacting diverse biological functions.
- Its role in various processes makes SETD8 a significant therapeutic target.
Purpose of the Study:
- To conduct comprehensive structure-activity relationship (SAR) studies on a series of SETD8 inhibitors.
- To discover novel quinazoline-based compounds with potent SETD8 inhibitory activity.
- To explore the impact of substituents at various positions of the quinazoline scaffold on inhibitory potency.
Main Methods:
- Synthesis and characterization of novel quinazoline derivatives.
- Biochemical and biophysical assays to evaluate SETD8 inhibitory activity.
- Structure-activity relationship (SAR) analysis of synthesized compounds.
Main Results:
- Identification of several new SETD8 inhibitors with potencies comparable to the lead compound UNC0379.
- Exploration of 2-, 4-, 6-, and 7-substituents on the quinazoline scaffold revealed significant SAR trends.
- Demonstrated selectivity for SETD8 over other methyltransferases.
Conclusions:
- The SAR studies provide valuable insights into the chemical space for developing potent and selective SETD8 inhibitors.
- New compounds identified represent promising leads for further drug development targeting SETD8.
- Understanding SAR trends facilitates the rational design of future therapeutic agents.
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