Targeted Protein Degradation: A New Generation of Therapeutics
Drugging the Undruggable
E3 ligases catalyze the transfer of ubiquitin onto a target protein. The presence of the ubiquitin tag destines the protein for destruction by the proteasome. Targeted Protein Degraders are small molecules that simultaneously bind an E3 ligase and a target protein to facilitate the transfer of ubiquitin onto that target protein thus causing its degradation. Because these molecules bind two different proteins simultaneously, we refer to them as Chimeric Targeting Molecules (CTMs). The structure of the CTM has three distinct regions: the E3 ligase binder (harness), the target protein binder (hook), and the linker.
CTMs have several potential advantages over traditional small molecule inhibitors:
1. Catalytic degradation
Standard inhibitors only block their target when they are bound to it, and each inhibitor molecule can only inhibit a single target. A CTM catalyzes the degradation of its target, and can do this over and over again, degrading multiple copies of its targets, thus increasing its potency.
2. Prolonged activity
Standard inhibitors are only active while they are bound to a protein’s active site and will fall off over time. CTMs catalyze the degradation of the protein, and the target needs to be resynthesized before it can be active again.
3. Complete elimination of target function
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 CTM catalyzes the degradation of the target thus eliminating all of its activities.
4. Oral administration
Given their ability to remove the targeted protein, CTMs are functionally more similar to genetic and RNA knockout or knock-down, which typically require injection or infusion. Our CTMs are designed to be administered orally, once daily.
5. Activity against resistant mutations
Standard inhibitors typically require very high affinity binding, and are susceptible to mutations at their binding site, particularly in cancer and infectious disease targets. CTMs can function with lower affinity binding, and our BTK degraders have demonstrated sustained activity in the presence of certain common resistance mutations.
6. Drugging the undruggable
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 CTMs.
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