Proximity-Based Modalities for Biology and Medicine

Abstract

Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of biological processes with high selectivity and has the potential to substantially expand the target space. A plethora of proximity-based modalities to target proteins via diverse approaches have recently emerged, opening opportunities for biopharmaceutical innovation. This Outlook outlines the diverse mechanisms and molecules based on induced proximity, including protein degraders, blockers, and stabilizers, inducers of protein post-translational modifications, and agents for cell therapy, and discusses opportunities and challenges that the field must address to mature and unlock translation in biology and medicine.

Figure 1

Mechanisms and modalities of induced proximity. Red words in parentheses represent the effector protein(s) recruited by the corresponding modality. RNA-PROTAC: RNA binding proteins targeting proteolysis-targeting chimera. TF-PROTAC: transcription factor targeting proteolysis-targeting chimera. PROTAB. proteolysis-targeting antibodies. PROTAC: proteolysis-targeting chimera. SNIPER: specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein erasers. BromoTag, dTAG, HaloPROTACs, auxin-induced degron (AID), and NanoLuc-targeting PROTACs (NanoTACs) are all genetically encoded fusion strategies for targeted protein degradation. HyT: hydrophobic tagging. CIDE: chemical inducers of degradation. HEMTAC: heat shock protein 90 (HSP90)-mediated targeting chimeras. CHAMP: chaperone-mediated protein degradation/degrader. AbTAC: antibody-based PROTACs. KineTAC: cytokine receptor-targeting chimeras. LYTAC: lysosome-targeting chimaeras. AUTAC: autophagy-targeting chimera. AUTOTAC: autophagy-targeting chimera. AceTAC: acetylation tagging system. PHIC: phosphorylation-inducing chimeric small molecules. PhosTAC: phosphorylation-targeting chimeras. PHORC: phosphatase recruitment chimeras. RIPR: receptor inhibition by phosphatase recruitment. RIPTAC: regulated induced proximity-targeting chimera. DUBTAC: deubiquitinase-targeting chimera. ENTAC: enhancement-targeting chimera. TF-DUBTAC: transcription factors targeting deubiquitinase-targeting chimera. RiboTAC: ribonuclease-targeting chimera. Cl-M6PR: cation-independent mannose-6-phosphate receptor. ASGPR: asialoglycoprotein receptor.

Figure 2

Representative structures of small-molecule proximity agents. The green moiety of the heterobifunctional structures binds to the target protein (in green caption), and the red moiety binds to effector protein (in red caption); the linker parts are shown in gray. The structures in blue are conventionally referred to as molecular glues, with their target proteins and effector proteins shown as green and red captions, respectively. The yellow structure is a homodimer.

Figure 3

Current approved or clinical-stage molecular glue (MG) degraders and perspective on new MG degraders. Prediction-based data from Drug Hunters.

Figure 4

Current PROTAC degraders in clinical studies and perspectives on future clinical-stage PROTAC degraders.

Figure 5

Perspectives on targeted protein post-translational modification.

Figure 6

Modalities of advanced cell therapy using proximity agents as ON and OFF switches. (A) CAR-engineered T Cells using Rimiducid as the ON and OFF switch. (B) CAR-engineered T Cells using lenalidomide as the ON and OFF switch.