A general chemical approach to lysine-directed probes for protein kinases

The challenges associated with developing new medicines are very significant indeed. The cost of bringing each new drug to the market 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 in 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 therapeutic 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 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.