Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is crucial for mitochondrial one-carbon metabolism.
• Elevated MTHFD2 expression is associated with poor patient survival in multiple cancers.

Purpose of the Study:

• To discover and characterize a novel, isozyme-selective inhibitor of MTHFD2 for potential cancer treatment.
• To identify a lead compound with high selectivity for MTHFD2 over its MTHFD1 counterpart.

Main Methods:

• High-throughput screening (HTS) was employed to identify initial hit compounds.
• Structure-based drug design (SBDD) was utilized to optimize the lead compound.
• Isozyme selectivity assays were performed to determine MTHFD2 vs. MTHFD1 inhibition.

Main Results:

• A novel inhibitor, DS44960156, with a tricyclic coumarin scaffold was identified.
• DS44960156 exhibits over 18-fold selectivity for MTHFD2 compared to MTHFD1.
• The inhibitor possesses a molecular weight under 400 and good ligand efficiency (LE).

Conclusions:

• DS44960156 represents a promising starting point for developing MTHFD2-targeted cancer therapeutics.
• The compound's high selectivity and favorable drug-like properties make it attractive for further optimization.