Abstract
Recently we reported the discovery of a potent and selective CK2α inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (αD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the αD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool. The work described herein shows potential for the development of a novel class of CK2 inhibitors.
Highlights
1.1 Fragment-based drug discoveryFragment-based drug discovery (FBDD) is a structure-based approach used to provide lead compounds to target biological systems
Initial hits usually have lower potency than those derived from High-Throughput Screening campaigns (HTS), Fragment-based drug discoveryFragment-based drug discovery (FBDD) is considered to be more efficient in the optimization phases of drug discovery.[1,2]
The linker should maintain the optimal binding configurations that have been adopted by the individual fragments and should establish additional interactions with the protein to prevent a loss in ligand efficacy (LE).[3]
Summary
1.1 Fragment-based drug discoveryFragment-based drug discovery (FBDD) is a structure-based approach used to provide lead compounds to target biological systems. In the growing strategy optimised fragment hit is grown in a step-wise fashion, engaging with the target through additional interactions.[3] The merging strategy sees the best features of several overlapping fragments merged into single molecule with higher potency.[3] In the linking strategy, fragments binding in different parts of the target site are linked together via rigid or flexible linkers.[4] The linked compound should have a more favourable ΔG of binding than the sum of the ΔG values of the individual fragments according to the concept of ‘super-additivity’.5-7 This last strategy has been considered to be the most difficult of the three methods applied in FBDD .3. In practise the linkers often constrain the molecule too much resulting in suboptimal interactions with the target
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