Biology subjects

Brown, G. A.

Publications and source records attributed to Brown, G. A..

3 recordsLinked to original sources

bioRxiv2026

Identification and SAR optimization of FBXO22-mediated TEAD Targeted Glue degraders

TEAD transcription factors are emerging oncology targets due to their function as key effectors of the Hippo signalling pathway, which is frequently dysregulated in cancer. Here, we report the discovery and development of potent, deep, and rapid-acting TEAD Targeted Glue degraders that leverage an aldehyde-mediated degron mechanism. Our compounds demonstrate exceptional on-pathway selectivity profiles and exhibit the expected Hippo signalling modulation. Mechanistically, we demonstrate that amine-based TEAD degrader scaffolds undergo extracellular conversion to the active aldehyde species, which mediate covalent engagement of FBXO22 C326, triggering TEAD proteasomal degradation. The degraders identified were able to be rationally and systematically optimised for both degradation potency and kinetics, achieving enhanced degradation profiles compared to previously reported FBXO22-targeting approaches, establishing design principles for this degrader class. Our findings highlight strategies for the structure activity relationship (SAR) and rational optimization of aldehyde-mediated degrons to generate novel precision molecular glue degraders against TEAD, a high value oncology target.

cancer biology↗

bioRxiv2025

Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of action elucidation and in vivo proof of concept

Prospective discovery of molecular glues degraders for a specific therapeutic target protein of interest is an emerging strategy in drug discovery. Modification of pre-existing ligands with fragments that can alter the protein surface can lead to the creation of novel compounds ( targeted glues) able to induce neo-interactions between the target and an E3 ligase, resulting in targeted protein degradation. By screening a library of potential BRD9 targeted glue compounds, we have discovered a potent and selective, reversibly covalent BRD9 degrader, AMPTX-1. Co-immunoprecipitation-mass spectrometry experiments demonstrated that cell treatment with AMPTX-1 induces selective recruitment of BRD9 to the E3 ligase DCAF16. Degradation is dependent on the engagement of the surface Cys58 of DCAF16 and formation of a covalent adduct to DCAF16 is facilitated by the ternary complex formation with BRD9. BRD9 degradation is achieved in vivo after oral dosing, demonstrating that covalent recruitment of DCAF16 is a viable strategy for targeted protein degradation and can be achieved with drug-like, orally bioavailable compounds with promising in vivo activity.

biochemistry↗

bioRxiv2020

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to 1 CA1 by differential modulation of feedforward inhibitory circuits

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations by facilitating synaptic plasticity. It is also proposed that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3, but this influential theory has not been directly tested. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, greater depression of feedforward inhibition from entorhinal cortex results in an overall enhancement of excitatory-inhibitory balance and CA1 activation. Underpinning the prioritisation of entorhinal inputs, entorhinal and CA3 pathways engage distinct feedforward interneuron subpopulations and depression is mediated differentially by presynaptic muscarinic M3 and M4 receptors respectively. These mechanisms enable acetylcholine to prioritise novel information inputs to CA1 during memory formation and suggest selective muscarinic targets for therapeutic intervention.

neuroscience↗