Developing a new drug costs over £2 billion and takes roughly 12 years, with more than 95% of candidates failing before reaching patients. This project tackles that attrition rate by building a faster, more general method for creating a specific class of drugs called covalent inhibitors—molecules that form a permanent chemical bond with their target protein, rather than simply fitting into it like a key in a lock. Most existing covalent inhibitors target a rare amino acid called cysteine, which limits which proteins they can attack. The researchers here target a different, more common amino acid—lysine—which is present in all 700 or so human protein kinases, many of which drive cancers and other diseases. They plan to develop a high-throughput chemical assembly line that links pairs of building blocks to produce diverse kinase probes, then make those probes openly available to the biomedical community, including Europe’s largest drug discovery unit. If successful, this approach could unlock chemical tools for hundreds of previously undruggable kinases, providing starting points for new medicines and allowing researchers to probe the fundamental biology of diseases. The work is primarily fundamental science—developing a general chemical strategy—but it directly addresses a bottleneck in drug discovery that keeps treatments from reaching patients.
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The challenges associated with developing new medicines are very significant indeed. The cost of bringing each new drug to the market is over £2 bn, in large part because of crippling (>95%) attrition rates in the drug discovery/development process. Even when successful, the process typically takes about 12 years from laboratory to patient. The pharmaceutical sector therefore faces the major challenges of increasing both productivity (by reducing costs and time-to-patient) and innovation (by finding drugs with new modes of action and/or for new disease areas). Most drug molecules function by modulating the function of a protein that is associated with disease. In most cases, these drugs bind into a pocket on the protein in a manner that is analogous to a key fitting into a lock. Recently, however, there has been a resurgence of drugs that function by forming a covalent bond to their target protein. Such drugs provide new therapeutical opportunities, and include ibrutinib (which treats cancers including chronic lymphocytic leukaemia) and nirmatrelvir (which treats COVID-19). Most commonly, covalent inhibitors are designed to target a nucleophilic cysteine, a strategy whose success relies on the presence of a suitable residue that is not susceptible to mutation. In this grant, we will develop a new chemical approach to drive the discovery of covalent inhibitors of specific protein kinases. The envisaged high-throughput synthetic approach will enable structure- and function-diverse kinase probes to be prepared by linking pairs of functionalized building blocks. Our approach is expected to be general because protein kinases contain a conserved lysine residue that may be capable of forming a direct connection to covalent inhibitor. Furthermore, the approach is expected to be important because the protein kinase class comprises around 700 different proteins, many of which are central to disease (including many cancers). It is envisaged that our approach will enable the discovery of useful chemical tools (which can be used to investigate the fundamental disease biology of specific protein kinases) and to provide new starting points for drug discovery. The approach therefore has the potential to unlock many new opportunities for addressing unmet patient needs. To maximise the impact of our approach, we will engage extensively with end-users of our research, including through a workshop and end-user-focused scientific meetings. To highlight its value to drug discovery and biomedical scientists, we will demonstrate that our approach can drive the discovery of specific chemical probes. We will make our probes openly available to the biomedical community (including Dundee Drug Discovery Unit, the largest such unit in Europe), enabling them to be exploited as chemical tools to address biomedical problems beyond this project. The availability of these chemical probes may provide new insights into disease biology that may be translated into drugs that benefit patients. In addition, drug discovery is a topic of great interest to the public, which will enable us to develop and deliver impactful public outreach activities.
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