Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• SMYD3 (SET and MYND domain-containing protein 3) is a histone methyltransferase.
• Overexpression of SMYD3 is linked to the development of various human cancers.
• Targeting SMYD3 offers a potential therapeutic strategy for cancer treatment.

Purpose of the Study:

• To identify and develop novel small molecules that inhibit SMYD3.
• To explore the potential of covalent inhibitors for targeting SMYD3.
• To evaluate the efficacy of newly discovered compounds in preclinical cancer models.

Main Methods:

• High-throughput screening to identify initial inhibitors.
• Structure-activity relationship studies for lead optimization.
• Biochemical assays to measure SMYD3 enzymatic activity.
• Cell-based assays, including 3D cell culture, to assess antiproliferative effects.

Main Results:

• A novel class of tetrahydroacridine compounds targeting SMYD3 was discovered.
• Optimization led to the identification of 4-chloroquinolines as potent covalent inhibitors.
• Tool compound 29 demonstrated high potency in inhibiting SMYD3 activity.
• Compound 29 exhibited significant antiproliferative effects against HepG2 cells in 3D culture.

Conclusions:

• Covalent inhibition of SMYD3 is a viable strategy for developing cancer therapeutics.
• The identified 4-chloroquinoline compounds represent a promising new class of SMYD3 inhibitors.
• Further research is warranted to explore the impact of covalent SMYD3 inhibition on gene expression and its therapeutic implications.