Advantages of TPD
Bivalent small molecule degraders have several potential advantages as therapeutics over traditional small molecule inhibitors with respect to:
Modulating “undruggable” targets
Some disease-related proteins cannot be easily targeted by traditional small molecule inhibitors due to the requirement for deep cavities/pockets to allow sufficiently strong binding for inhibition. By contrast, degradation can take place with TPDs without the need for such strong binding, allowing expansion to targets traditionally considered undruggable by small molecule occupancy-driven models.
Blocking all protein functions
Typically, small molecule inhibitors will only block a specific function of a protein target but not all of its other functions, some of which may also be relevant to the disease process.
Lower dosing due to their catalytic nature
Traditional inhibitors only function when they are bound to a target, and each inhibitor can only block the activity of a single target. However, bivalent degraders work catalytically to degrade multiple targets, thus much lower doses can be used than required to obtain the same therapeutic effect with a traditional small molecule.
Traditional inhibitors only function when they are bound to a protein’s active site. Protein degraders actually remove the target from the cell, potentially producing a longer-lasting biological effect.
Reduced drug resistance
Traditional inhibitors usually require high affinity binding and can be liable to mutations at their binding sites. Protein degraders perform with low affinity binding, which is hypothesised to make them less susceptible to resistance mutations.
What makes Ligature Therapeutics different?
Our FBDD Engine
Taking an agile approach to the design and development of a portfolio of potent, heterobifunctional TPDs allows us to overcome the development limitations of the first generation of these molecules. Our unique FBDD Engine incorporates a suite of highly sensitive, high resolution biophysical techniques that are independent of crystal structures, allowing us to rapidly manipulate our library of binders and degraders and quickly identify the binders with the most potential.
Our tumor-selective targeted protein degrader strategy
Ligature understands that relying on a limited number of E3 ligases restricts the potential scope of current degrader approaches. By proactively identifying E3 ligases that are underexploited but highly expressed in specific tissues or tumor types and matching these to complementary cancer target proteins, we are designing TPDs that provide two layers of tumor-specificity in one potent, functionally designed molecule.