A practical method for determining the rate of covalent modification of fragments and leads.

ABSTRACT: The clinical success of covalent drugs such as sotorasib has renewed interest in covalency for rational drug design. The most rigorous potency metric for covalent modifiers is the second-order rate constant k_inact/K_I. However, existing methods for measuring k_inact/K_I are resource-intensive and involve complex data interpretation. We describe the diagonal dose-response time-course (dDRTC), an efficient mass spectrometry-based method for determining k_inact/K_I, enabling routine k_inact/K_I quantification earlier in programs and accelerating SAR interpretation for lead discovery. We apply dDRTC to a dozen covalent fragment and lead-like modifiers for three targets, KRAS^G12C and two E3 ligase comple

SUBMITTER: Jeon J 

PROVIDER: S-EPMC12714714 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature