Trends in Pharmacological Sciences
OpinionCritical Assessment of Targeted Protein Degradation as a Research Tool and Pharmacological Modality
Section snippets
Overview of Small Molecule Drug Discovery
If measured by the number of FDA approvals, 2018 was a remarkable year. A record-setting 59 new drugs were approved, including the first small interfering RNA-based drug [1,2]. This continued the trend of approvals for novel pharmacological modalities, such as the first gene therapy [3] and the first cell therapies [4] approved in the previous year. Moreover, biologics approved in 2018 constituted almost 30% of the total number of approved drugs, close to 40% of the pipeline, and a steadily
Targeted Protein Degradation as a Pharmacological Modality
Targeted protein degradation is not an unprecedented mode of action given that thalidomide, a drug with a troubled history of birth defects and currently in use as a treatment for multiple myeloma and leprosy [14], acts by inducing targeted degradation of several transcription factors by recruiting them to an E3 ligase called cereblon (CRBN) [15]. In the case of thalidomide, the exact mechanistic insight into how this drug exerts its effects emerged some six decades later after its initial use
SWOT-Based Strategic Analysis
Given the growing enthusiasm for targeted protein degradation research, we will use this opinion article as an opportunity to take a step back and highlight our views on strategic priorities for the next several years. To help us frame the discussion, we will employ a Strengths-Weaknesses-Opportunities-Threats (SWOT) analysis, which is a widely used business development and strategic planning tool. In that context, the results of SWOT analyses are used to formulate key actionable points that,
Concluding Remarks
Targeted protein degradation is an exciting therapeutic modality that addresses the key reason for attrition in clinical trials: lack of efficacy in Phase II. In theory, a degrader will deliver enhanced efficacy and more closely mimic genetic methods of whole protein depletion. The field is developing at a remarkable pace and there has been considerable investment in biotech and pharma companies to further exploit targeted protein degradation [67].
Our SWOT analysis (Figure 4) highlights not
Acknowledgments
M.K. is supported by the Linde Program in Cancer Chemical Biology and the NCI T32 CA236754. M.K. also acknowledges attendees of the 1st Proteome-Targeted Drug Discovery Summit 2019 for very helpful discussion.
Disclaimer Statement
M.K. is a paid consulting editor at Life Science Editors. L.H.J. receives funding from Deerfield.
Glossary
- Hook effect
- phenomenon observed for PROTAC degrader molecules (and previously documented for antibodies), where the effects decrease with increasing concentration of the degrader past a certain peak point. This is due to higher concentrations of PROTACs favoring binary complex formation, rather than ternary resulting in ‘hook’-shaped activity versus concentration curve.
- Lipinski’s ‘rule-of-5’ (Ro5)
- an empirical set of rules which states that poor absorption or permeation is more likely when a
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