George Kumar: Stabilizing Molecular Complexes May Unlock Undruggable Targets
George Kumar, Senior Director at AstraZeneca, shared a post on LinkedIn about a paper by Raymond J. Deshaies et al. published on Science:
“What if the best way to treat disease isn’t by blocking interactions – but by locking them in place?
Load and lock: An emerging class of therapeutics that influence macromolecular dissociation
Cells depend on countless molecular interactions that are constantly forming and breaking apart. Each interaction has:
- kon – how fast partners bind
- koff – how fast they fall apart
- KD – the balance, or affinity
For many processes, fast dissociation (high koff) is essential – like kinesin ‘walking’ along microtubules. But in other cases, extending the lifetime of a molecular complex can supercharge signaling, as seen with ligand–receptor binding.
Traditionally, drugs disrupt interactions by lowering binding (reducing kon), such as kinase inhibitors that compete with ATP. But this approach often fails against ‘undruggable’ targets like transcription factors.
Enter LOCKTACs
Instead of blocking, these molecules stabilize macromolecular complexes – prolonging their lifetime and unlocking new ways to modulate biology.
This shift – from inhibiting to stabilizing – could open up whole new frontiers in drug discovery.
Figure Courtesy: Science and Raymond J. Deshaies. Amgen Research, Thousand Oaks, CA, USA.”
Title: Load and lock: An emerging class of therapeutics that influence macromolecular dissociation
Authors: Raymond J. Deshaies and Patrick Ryan Potts
Read the full article.
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