Taking stock of 26 emerging protein degradation companies, what innovative trends do they reveal?

At present, the research and development of protein degradation therapy faces multiple challenges
.
The first wave of clinical-stage protein-degrading drugs targeted mature targets that had already been clinically validated, such as the androgen and estrogen receptors
selected by Arvinas.
The real potential of protein degradation therapy lies in reaching targets that are difficult or non-druggable in current treatment models, and are still in the exploration stage
.
Understanding which targets are ideal targets for protein degradation therapy is one of
the main challenges to be addressed.
Gebo Bio has built a molecular gel and new target discovery technology platform, which improves the discovery success rate and optimization efficiency
of molecular gel drugs through high-throughput screening, multi-omics and structural biology, and rational design tools such as machine learning and degradation unit prediction for a variety of "undruggable" pathogenic protein targets 。 Dunad Therapeutics' unique small molecule platform has the potential to develop oral bioavailable and central nervous system available degradation therapies by directly modifying targets with monovalent small molecules to induce targeting of normally undruggable degradation pathogenic proteins, and to expand the frontiers
of protein degradation targets.
Due to the three-component chimera structure of PROTAC molecules, the molecular weight is large, resulting in the development of most PROTAC molecules facing pharmacokinetic (PK) characteristics, low solubility and cell permeability, low oral bioavailability and other druggability challenges
.
Many disease-associated proteins carry intrinsic disordered regions that conventional small molecule drugs cannot target, yet thousands of proteins with such intrinsically disordered regions have been found to interact
with adaptor proteins called 14-3-3.
When binding to a disordered protein region, the 14-3-3 protein can induce the disordered protein to form a stable structure that binds to it, giving them druggability
.
Ambagon Therapeutics applies in-depth knowledge of 14-3-3 proteins and a proprietary set of drug discovery tools to create molecular glues
that stabilize the complex structure of 14-3-3 and interacting proteins.
At the same time, although the design of PROTAC molecules based on the recruitment of CRBN and VHL ligase has become increasingly mature, their preclinical and clinical development still faces multiple challenges, and the potential to target protein degradation has led both academia and the pharmaceutical community to explore new E3 ligases
.
Pin Therapeutics selected about 30 E3 ligases suitable for drug development from a total of about 600 E3 ligases through analysis, and established a platform technology to efficiently identify E3 ligases
with improved drug properties in a short period of time.
Triana Biomedicines' drug discovery engine searches for 600 different E3 ligases and selects the best E3 ligase for drug development
based on indications and targets.