Covalent inhibitor drugs: From serendipity to rational technology
Van Leeuwenhoek Lecture on BioScience.
Tjeerd Barf is one of the founders of Acerta Pharma. He has extensive experience in Pharmaceutical Research and Development and contributed to delivery of several clinical candidates in the metabolic disease, autoimmune and oncology space. He successfully exploited the covalent binding paradigm for kinases, resulting in the discovery of acalabrutinib. Tjeerd joined the pharmaceutical industry in 1997 and served in various project and line management roles at Pharmacia & Upjohn, Biovitrum, Organon, Schering-Plough and MSD. He holds a PhD in Medicinal Chemistry and MSc in Organic Chemistry from the University of Groningen.
Covalent binding technology aims to equip drug-like small molecules with a suitable chemical reactive group. This reactive group adducts specific protein targets of which the (over)activity is believed to be central to the control of a certain disease. After reaction, the drug is covalently bound to the protein, resulting in long-lasting inhibition. Consequently, only the regeneration (de novo synthesis) of the protein can restore its function. Whereas continuous circulation of conventional reversible binding drugs is generally essential, the presence of covalent drugs - once bound to the protein - is not needed to exert the beneficial effects. The target family of kinases, despite the lack of obvious reactive amino acid counterparts, can be exploited using the covalent binding technology as witnessed by the recent successful discovery of covalent BTK inhibitor acalabrutinib for the retreatment of certain blood cancers.