Christine Ng

All Publications

• Targeted protein relocalization via protein transport coupling. Nature Ng, C. S., Liu, A., Cui, B., Banik, S. M. 2024

  Abstract

  Subcellular protein localization regulates protein function and can be corrupted in cancers1 and neurodegenerative diseases2,3. The rewiring of localization to address disease-driving phenotypes would be an attractive targeted therapeutic approach. Molecules that harness the trafficking of a shuttle protein to control the subcellular localization of a target protein could enforce targeted protein relocalization and rewire the interactome. Here we identify a collection of shuttle proteins with potent ligands amenable to incorporation into targeted relocalization-activating molecules (TRAMs), and use these to relocalize endogenous proteins. Using a custom imaging analysis pipeline, we show that protein steady-state localization can be modulated through molecular coupling to shuttle proteins containing sufficiently strong localization sequences and expressed in the necessary abundance. We analyse the TRAM-induced relocalization of different proteins and then use nuclear hormone receptors as shuttles to redistribute disease-driving mutant proteins such as SMARCB1Q318X, TDP43ΔNLS and FUSR495X. TRAM-mediated relocalization of FUSR495X to the nucleus from the cytoplasm correlated with a reduction in the number of stress granules in a model of cellular stress. With methionyl aminopeptidase 2 and poly(ADP-ribose) polymerase 1 as endogenous cytoplasmic and nuclear shuttles, respectively, we demonstrate relocalization of endogenous PRMT9, SOS1 and FKBP12. Small-molecule-mediated redistribution of nicotinamide nucleotide adenylyltransferase 1 from nuclei to axons in primary neurons was able to slow axonal degeneration and pharmacologically mimic the genetic WldS gain-of-function phenotype in mice resistant to certain types of neurodegeneration4. The concept of targeted protein relocalization could therefore inspire approaches for treating disease through interactome rewiring.

  View details for DOI 10.1038/s41586-024-07950-8

  View details for PubMedID 39294374

  View details for PubMedCentralID 7429473

• Recent advances in induced proximity modalities. Current opinion in chemical biology Ng, C. S., Banik, S. M. 1800; 67: 102107

  Abstract

  Challenging disease targets necessitate new approaches for therapeutic intervention. Rewiring protein-biomolecule interactions with proximity-inducing agents extends intervention opportunities beyond target agonism or inhibition. Spanning varied molecular phenotypes and diverse target classes, proximity-inducing agents demonstrate immense potential across target degradation, cleavage, and post-translational editing. Here, we review a selection of exciting developments in the concepts and mechanisms of induced proximity-driven strategies from the last two years. Key technological advances that enable these discoveries and expand the scope of targets and machinery for induced-proximity modalities are highlighted.

  View details for DOI 10.1016/j.cbpa.2021.102107

  View details for PubMedID 35033823

• Taming transcription factors with TRAFTACs. Cell chemical biology Ng, C. S., Banik, S. M. 2021; 28 (5): 588-590

  Abstract

  Transcription factors play central roles in numerous diseases yet are notoriously challenging targets for drug development. In this issue of Cell Chemical Biology, Samarasinghe etal. (2021) describe a modular approach to targeting transcription factors for degradation with TRAFTACs, without the need for extensive ligand development campaigns.

  View details for DOI 10.1016/j.chembiol.2021.04.016

  View details for PubMedID 34019844