Harnessing TPD’s Advantages to Overcome the Limits of Inhibition
Many targeted therapies work by binding to and inhibiting a disease-causing protein. While these small molecules offer therapeutic benefits to patients, inhibitors are widely recognized to have limitations.
One of these constraints is that inhibition requires an active site, which means that inhibitors only work if they bind to a site on the target protein that blocks an essential function. Resistance is also a limitation—after prolonged use, many proteins develop mutations in this active site which cause inhibitors to lose their effect over time. Additionally, because inhibition requires that active-site to be blocked at all times, full inhibition only occurs when there are at least as many inhibitor molecules as there are target proteins. This means that high concentrations of an inhibitor medicine can be required to generate the desired effect; however, those high concentrations can result in the inhibitor impacting other healthy tissues in the body and cause side-effects. Another constraint is what happens when an inhibitor is removed or metabolized: Because the target proteins are still present, disease-causing activity often resumes.
TPD has the potential to overcome some of the limitations of inhibitors.
Bind to any surface on a disease-causing protein
Degraders can bind to any surface on a disease-causing protein, rather than only an active site. The ability to bind to any surface means degraders have the potential to address targets that are not reachable by current inhibitor therapies.
Degraders act on multiple copies of the disease-causing protein
Degraders can remove many copies of the disease-causing protein, rather than just blocking a single protein, resulting in relatively lower doses, limiting the opportunity for off-target effects.
Degraders can have a lasting effect even after the medicine is cleared from the body because the only way for protein function to return is through protein resynthesis. This prolonged effect offers the potential to treat patients with a lower or less frequent dose.
Inhibitors rely on constantly occupying their binding site. As such, they are highly vulnerable to mutations in this site that weaken binding and reduce occupancy. Inhibitors are also vulnerable to mutations that occur elsewhere in the target protein that allow it to overcome inhibitory effects. Both types of mutation can lead to inhibitor resistance. Degraders can overcome these mechanisms because degradation removes all target protein functions and is not as dependent on sustained occupancy of the binding site.
Specificity to the disease-causing protein
Degraders are often more specific for the desired target protein than inhibitors since a degrader not only needs to bind the target, it also needs to form a ternary complex in a specific orientation to promote efficient ubiquitination. These additional steps in the degradation process act as a filter to increase selectivity. This makes degraders more precise medicines with fewer off-target interactions that can lead to adverse side effects.