The Dana-Farber Cancer Institute utilized SWOT analysis to targeted protein degradation drug development to better evaluate the approach's strengths, weaknesses, opportunities, and threats.

SWOT (Strengths-Weaknesses-Opportunities-Threats) analysis is frequently used in business development and strategic planning, but it may also be used to critically analyze quickly evolving fields, as the Dana-Farber Cancer Institute has done with targeted protein degradation (TPD).

Strengths

* The ability of POI (protein of interest) can be directly "knocked out" via targeted protein degradation, which is quick and reversible, making it a good complement to genetic techniques like CRISPR/Cas9.

* Targeted degradation is emerging as a valuable approach to preclinical target validation, and TPD molecules have advantages over other small molecule drugs for several reasons, such as:

* TPD compounds don't need to be tightly bound to have an impact, therefore they could be used for POIs that don't have a defined small molecule binding pocket, providing an opportunity for "non-druggable" POIs.

* TPD molecules generally have better selectivity than inhibitors because it relies on degradation molecules, POIs, and E3 ligases to form complexes, reducing the non-specific effects of non-complexed degradation molecules.

* TPD is more likely to be successful. Although the clinical efficacy of PROTAC-based compounds has yet to be established, preclinical research suggests that these molecules can act at lower dosages and for longer periods of time.

Weakness

* One of the most frequently cited disadvantages of PROTACs is that they do not comply with Lipinski's "Rule of 5" (Ro5). PROTACs in clinical trials are orally bioavailable and new dosage forms need to be developed to support this. Clear design rules and principles are lacking, and the field remains largely empirical.

* For targets without known scaffold function, it is not possible to predict whether degradation strategies will provide an efficacy advantage over inhibition.

* Although the human genome encodes approximately 600 E3 ligases (not all of which mediate ubiquitination), there are currently fewer types of E3 ligases available for PROTAC-mediated targeting, concentrated in CRBN and VHL, and further research is needed to expand the E3 ligase pool.

* PROTAC activity is similarly characterized by a classic bell-shaped concentration dependence ("Hook effect"). PROTAC molecules can saturate the binding sites on POI or E3 ligases at high concentrations, preventing the formation of the required ternary complexes. As a result, activity decreases and induced degradation is inhibited.

Opportunities

* Small molecule degraders, including "molecular gels" and PROTACs, are becoming powerful research tools for the proteome.

* Hormone receptors, kinases, and bromodomain are now the most common drug targets for PROTACs, while molecular gels mostly target transcription factors, and the pharmacologically relevant degradable proteome is likely to become a novel target in the future.

* Chemically induced dimerizers (CIDs) are compounds that cause two proteins to chime together to generate dimeric chimeras with distinct functions. TPD is a CID based on the conversion of small molecules that recruit ubiquitin ligases to small molecules that recruit phosphatases to achieve phosphorylation for POIs, allowing for particular post-translational changes of the protein.

Threats

* The ubiquitin-proteasome system, the function of degraded molecules, and other biological understandings are all lacking. Most targeted degradation studies are currently focused on how to get into the clinic as quickly as possible, and basic studies such as new ubiquitin ligase substrates, distribution and physiological functions of degraded proteins, epigenetic changes after TPD use, and drug resistance mechanisms are not being thoroughly investigated.

* RNAi drug research was once assumed to be omnipotent, with the ability to achieve druggability for all targets, but this was not the case. TPD was also utilized as a lifesaver for targets that couldn't be drugged, but clinical development was slower than expected, and we may have eventually discovered that it was only suitable for individual targets.