Precision Medicine Approaches for the Modulation of Target Proteins

Abstract

Precision medicine has emerged as a transformative approach in healthcare, enabling tailored treatments based on genetic, lifestyle, and environmental factors. To advance this field, new drug modalities are needed that precisely target molecular drivers of disease while minimising off-target effects. Traditional discovery approaches, however, are often slow and costly.

Following the Human Genome Project, innovative design strategies have expanded the scope of precision medicine. Among these, bifunctional molecules such as PROTACs, PHICS, and AceTACs have gained prominence for modulating protein function via post-translational modifications, moving beyond the binary activation–inhibition paradigm. In parallel, covalent chemistry targeting non-conserved cysteine residues offers isoform-selective precision medicines, exemplified by ritlecitinib (Litfulo), a first-in-class covalent JAK3 inhibitor.

This thesis explores new therapeutic scaffolds based on bifunctional molecules and covalent inhibitors. A novel series of degraders was designed, synthesised, and evaluated in vitro against breast cancer-relevant proteins including Akt, CDK2, and sirtuins. From this work, the sirtuin-targeting degrader led to the conceptualisation of DeAceTAC, a modality designed to selectively induce deacetylation of proteins such as PTEN and Akt, which are critical in breast cancer pathophysiology.

In parallel, potent covalent inhibitors of Pyk2 were developed as antiplatelet agents. The lead candidate showed selective inhibition of Pyk2, sparing its paralogue FAK, essential for normal haemostasis. In preclinical models, these inhibitors enhanced the clot-busting efficacy of tissue plasminogen activator (tPA) without increasing bleeding risk.

Collectively, this work demonstrates the potential of bifunctional and covalent strategies to advance next-generation precision medicines for complex diseases, from breast cancer to thrombotic stroke.