Multiparameter kinetic analysis for covalent fragment optimization using quantitative irreversible tethering (qIT)

DOI: 10.1002/cbic.202000457

Authors: Gregory B. Craven (Imperial College London) , Dominic P Affron (Imperial College London) , Teresa Kösel (Imperial College London) , Tsz Lam M Wong (Imperial College London) , Zoë H Jukes (Imperial College London) , Chun-Ting Liu (Imperial College London) , Rhodri M L Morgan (Imperial College London) , Alan Armstrong (Imperial College London) , David J. Mann (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chembiochem

State: Published (Approved)
Published: July 2020
Diamond Proposal Number(s): 17221

Abstract: Covalent fragments are increasingly being implemented to develop chemical probes but the complex relationship between fragment structure and binding kinetics makes optimization uniquely challenging. We describe a new technique in covalent probe discovery that enables data driven optimization of covalent fragment potency and selectivity. This platform extends beyond the existing methods for covalent fragment hit identification by facilitating rapid multiparameter kinetic analysis of covalent structure‐activity relationships through simultaneous determination of Ki, kinact and intrinsic reactivity. We apply this approach to develop novel probes against electrophile sensitive kinases and showcase how multiparameter kinetic analysis enabled a successful fragment merging strategy.

Journal Keywords: Covalent fragments; Cdk2; Fragment-based drug discovery; Irreversible inhibition kinetics; Electrophile-sensitive inhibition

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 22/07/2020 09:52

Discipline Tags:

Biochemistry Chemistry Structural biology Biophysics Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)