Selective CTPS1 Inhibitor Scaffolds to Reduce Toxicity

The patent segments the CTPS enzyme into two distinct isozymes (CTPS1 and CTPS2) with different functions and tissue distributions. By designing inhibitors that selectively target CTPS1 rather than both isozymes, the therapy achieves effective inhibition of nucleotide synthesis in immune cells while sparing other tissues that rely on CTPS2, thereby reducing toxicity.

The invention applies local quality by creating inhibitors with specific molecular structures (e.g., pyrimidine-based scaffolds with particular substituent patterns) that bind preferentially to CTPS1's active site. This structural specificity ensures the inhibitor acts locally on CTPS1 without affecting CTPS2, achieving targeted therapeutic action with reduced systemic toxicity.

The patent employs parameter changes by modifying molecular properties of the inhibitor compounds, such as introducing specific heterocyclic rings (pyrimidine, pyrazine), adjusting substituent positions and types (halogens, alkyl groups, sulfonamides), and optimizing hydrogen bonding capabilities. These parameter adjustments create high affinity for CTPS1 while maintaining lower affinity for CTPS2, achieving the required selectivity.

The invention uses structure-activity relationship (SAR) analysis to create a series of inhibitor compounds that copy and refine the binding mode of naturally occurring CTPS1 substrates or transition state analogs. By iteratively optimizing molecular structures based on binding interactions, the patent develops compounds with enhanced CTPS1 selectivity while maintaining inhibitory potency.