CTPS1-Selective Inhibitor Structure for Reduced Off-Target Toxicity
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Solution Overview
Problem
Current therapies targeting nucleotide synthesis pathways, particularly those inhibiting cytidine triphosphate synthase 1 (CTPS1), suffer from non-selectivity and toxicity issues, limiting their efficacy in treating immune and cancer-related pathologies.
Innovation Solution
Development of a selective CTPS1 inhibitor, N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide, with a 2-30 fold selectivity for CTPS1 over CTPS2, for use in treating conditions associated with T-cell and B-cell proliferation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective CTPS inhibitors are used to treat immune and cancer-related pathologies, then nucleotide synthesis is inhibited, but selectivity is poor and toxicity increases
Solution Approach 1:
The patent applies local quality by designing a molecule with distinct functional domains that interact with specific residues in the CTPS1 active site. The compound features a pyrimidine ring system with specific substituents (ethoxypyrazinyl group at position 2, ethylsulfonamido group at position 4) that create localized interaction zones with CTPS1, enabling selective inhibition without affecting CTPS2. This localized molecular design allows the inhibitor to target specific pathological processes while sparing normal cellular functions.
Solution Approach 2:
The patent employs parameter changes by optimizing the chemical structure of the inhibitor to achieve 2-30 fold selectivity for CTPS1 over CTPS2. By modifying molecular parameters such as the introduction of the ethylsulfonamido group and ethoxypyrazinyl substituent, the compound's binding affinity and selectivity are tuned to specifically inhibit CTPS1 while maintaining acceptable pharmacokinetic properties and reduced toxicity.
2Adaptability or versatility
If CTPS1 is inhibited to reduce T-cell and B-cell proliferation, then immune-related pathologies are treated, but off-target effects may occur
Solution Approach 1:
The patent applies segmentation by dividing the CTPS enzyme into two distinct isozymes (CTPS1 and CTPS2) with different tissue distributions and functional roles. The inhibitor is specifically designed to target CTPS1, which is highly expressed in activated lymphocytes and certain cancer cells, while sparing CTPS2 that maintains essential CTP levels in normal tissues. This segmentation approach allows selective suppression of pathological cell proliferation while preserving normal immune function and cellular metabolism.
3Measurement precision
If selective CTPS1 inhibitor is developed, then selectivity for CTPS1 over CTPS2 is improved, but compound complexity increases
Solution Approach 1:
The patent applies the taking out principle by extracting and optimizing the key pharmacophoric elements responsible for CTPS1 selectivity from a broader class of CTPS inhibitors. The molecular design focuses on essential features (pyrimidine core with specific positional substituents) that confer selectivity, while eliminating unnecessary complex moieties. This extraction approach achieves 2-30 fold selectivity with a relatively streamlined structure that maintains drug-like properties.
Data Source
AI summary
Compounds of formula (I) as human cytidine triphosphate synthase 1 ( CTPS1) inhibitors for the treatment of proliferative diseases, such as e.g. cancer, such as e.g. leukemia and lymphoma, e.g. inflammatory skin diseases such as psoriasis, or e.g. multiple sclerosis. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. pages 64 to 80; examples; biological examples 1 and 2; e.g. compounds P140, P231 to P263; tables 1 to 10). Specific examples are e.g.: N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(methylsulfonamido) pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide (Formula (II)), or 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6- ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (Formula (III)).