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Are We Ready to Formulate the Next Generation of Small Targeted Therapeutics?

The drug discovery pipeline is currently bursting with innovative small and medium sized modalities and targeted therapies. Progress in molecular biology and genome sequencing is fuelling the next wave of drug discovery advancements, re-inventing the space for small molecules through adding new mechanisms of action such as targeted protein degradation (TPD) previously only thought possible with larger protein and antibody therapeutics. Upon their discovery, monoclonal antibodies have revolutionised the biopharmaceutical market due to their enhanced pharmacokinetic profile and high selectivity and binding capability to extracellular targets (Pei et al., 2019). With antibodies, though, it is difficult to target intracellular proteins/targets due to their large molecular size.

Shift towards druggability optimisation

Despite their phenomenal success, years of research have not yet unravelled the dilemma associated with druggability of many pathogenic targets and complete selectivity and safety of biologic treatment modalities. In fact, many compelling drug targets are yet to be drugged as 85% of the disease-causing proteins are believed to remain unexploited with the current large molecule approaches (Neklesa et al., 2017). Therefore, a paradigm shift towards druggability optimisation has been noticed, in quest for molecules that serve as an extension of the oral druggable space. Ideally, these molecules possess the best of all preceding therapeutics, with drug-like characteristics of small molecules and selectivity of monoclonal antibodies and gene therapy (Neklesa et al., 2017).

It is noteworthy that Lipinski’s rule of five served as a rule-of-thumb for the selection of drug candidates with the potential of oral administration. However, the time has come to exploit molecules with drug-like properties far beyond these boundaries. PROTACs, or proteolysis targeting chimeras, come into play with their unique mode of action that distinguishes them from other therapeutic modalities. They induce the degradation of pathogenic proteins by utilising the body’s natural protein disposal machinery known as ubiquitinproteasome system (Pei et al., 2019). PROTACs can unlock the undruggable space as they behave in a catalytic manner that is based on a transient interaction rather than constant, sustained binding. PROTACs tend to knockdown the target at lower doses compared to small molecule inhibitors, thus potentially minimising dose-related toxicity (Chen et al., 2023).

Any Delivery or Formulation Challenges?

It seems that PROTACs intrinsically address the delivery challenges associated with the previously discussed therapeutic modalities as they seem to be more selective. However, our experience from a formulation perspective shows a number of challenges with these type of molecules despite their intricate molecular design. In fact, PROTACs possess challenging physiochemical properties as they fall within the chemical space of what is called the beyond-the-rule of five space (Bro-5 for short, Figure 1 shows an example of one of these molecules, MZ1) (Madan et al., 2022). Because of the properties imposed by this chemical space such as their high molecular weight, polar surface area, and high lipophilicity, PROTACs come with their own set of challenges, namely poor cellular permeability, poor aqueous solubility, and subsequently low oral bioavailability (Chen et al., 2023). They are also characterised with molecular flexibility, better described as chameleonicity, which adds to their complexity and may account for changes in their physicochemical properties depending on their conformation (Yokoo et al., 2023). Yet, two Oral PROTACs, ARV 110 and ARV 471, managed to reach phase two clinical trials in 2022, reflecting the promising balance of efficacy and pharmacokinetic/ CMC profile of these molecules (Yokoo et al., 2023).