Table Info

Table 1.

Clinically relevant advantages and limitations of PROTAC degraders compared to small molecule inhibitors

Features	PROTAC degraders	Small molecule inhibitors
Pharmacodynamic profile	Active in inhibitor-resistant cancer models [4, 44]	Acquired resistance is common [1, 44]
Selectivity	More selective and less off-target toxicity [3, 5, 45–47]	Side effects due to off-target toxicity [3]
Pharmacokinetic profile	Sustained target degradation and less frequent dosing [4]	Reversible target binding is common with frequent dosing [1]
Scope of application	Tolerate low affinity target binding for action; target protein complexes [6]	Require high affinity binding to protein target [6]
ADME	Higher molecular weight and potentially poor penetration to the cells; complex design may lead to rapid drug metabolism and excretion [4, 7]	ADME profile can be readily optimized [4]
Resistance mechanism	Complex design can be associated with multiple mechanisms of resistance [9]	Often due to point mutations at the binding pocket of protein target [4]

ADME: absorption, distribution, metabolism, and excretion

Declarations

Author contributions

HX, JL and DMAG wrote the first draft of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

The support grant to Dr. Hao Xie was from H. Lee Moffitt Cancer Center & Research Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

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