Targeted Protein Degraders have several potential advantages over traditional small molecule inhibitors:
Standard inhibitors only block their target when they are bound to it, and each inhibitor molecule can only inhibit a single target. A protein degrader catalyzes the degradation of its target, and can do this over and over again, degrading multiple copies of its targets, thus increasing its potency.
Standard inhibitors are only active while they are bound to a protein’s active site and will fall off over time. A degrader catalyzes the degradation of the protein, and the target needs to be resynthesized before it can be active again.
Certain targets have multiple activities. For example, a signaling molecule may have an enzymatic function and a structural function. Standard inhibitors may only disrupt the enzymatic function, leaving other functions uninhibited. A degrader catalyzes the degradation of the target thus eliminating all of its activities.
Given their ability to remove the targeted protein, degraders are functionally more similar to genetic and RNA knockout or knock-down, which typically require injection or infusion. Our degraders are designed to be administered orally, once daily.
Standard inhibitors typically require very high affinity binding, and are susceptible to mutations at their binding site, particularly in cancer and infectious disease targets. Degraders can function with lower affinity binding, and our BTK degraders have demonstrated sustained activity in the presence of certain common resistance mutations.
Some disease-causing proteins, such as structural proteins and protein complexes, are not amenable to standard inhibitors. We believe these targets can be addressed using degraders.