Covalent lysine binder library

ChemDiv’s library of the small molecule covalent lysine binders contains 4,200 compounds.

The utilization of covalently binding inhibitors is currently demonstrating a significant steady increase, with an array of molecules going through various phases of clinical trials and some even achieving the status of marketed pharmaceuticals [1]. Presently, cysteine (Cys) and serine (Ser) are predominantly targeted for the development of covalently bound inhibitors [2], primarily due to their highly nucleophilic side chains, thiolate and alcoholate, respectively, which are active under physiological conditions. However, cysteine is relatively rare in both protein sequences overall and at protein surfaces, in particular. In contrast, serine, when not part of a catalytic site, is less likely to lose its proton, making it a less reactive target. Consequently, there is an ongoing effort to explore the selective targeting of other amino acid side chains for inhibitor binding. Lysine, being more abundantly present in protein binding sites compared to cysteine, emerges as a promising candidate for the rational design of targeted covalent inhibitors (TCIs) [1]. The primary challenge lies in lysine's lower nucleophilicity and its usual protonated state under physiological conditions. Nonetheless, significant variations in the pKa values of lysine residues have been observed, influenced by their surrounding environments [3]. This variability presents an opportunity to enhance the likelihood of achieving productive and targeted covalent interactions.

Covalent lysine binding compounds represent a novel approach to drug discovery, exploiting the abundant presence of lysine in protein binding sites to develop targeted therapies. By forming a covalent bond with lysine residues, these compounds offer the potential for creating highly selective and potent inhibitors that can modulate protein function with enhanced stability and a prolonged duration of action. This specificity is particularly valuable in designing drugs that can tightly and irreversibly bind to their targets, reducing off-target effects and improving therapeutic efficacy. The ability to target lysine residues also opens new avenues for the rational design of drugs against a broader range of proteins that were previously challenging to target, thus expanding the scope of treatable diseases and conditions.

Covalent lysine binders hold significant promise across a range of therapeutic areas, with particular potential in oncology, infectious diseases, neurodegenerative disorders, inflammatory conditions, and metabolic disorders. In oncology, they offer a pathway to selectively inhibit cancer-promoting proteins, potentially reducing the incidence of drug resistance and side effects. For infectious diseases, they could lead to novel antimicrobials and antivirals that target essential pathogen proteins, addressing antibiotic resistance. In the realm of neurodegenerative diseases, targeting proteins involved in toxic aggregation offers a novel strategy to combat conditions like Alzheimer's and Parkinson's diseases. For inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, covalent lysine binders could provide more specific and safer treatments. Lastly, in metabolic disorders, they have the potential to modulate key enzymes involved in diabetes and obesity, offering new therapeutic avenues. This broad applicability underscores the transformative potential of covalent lysine binders in modern medicine.

In our library, we have compiled structures featuring electrophilic warheads that exhibit a preference for binding to lysine, intended for use in the initial stages of drug discovery. This compilation aims to support the initial phases of drug discovery. The most comprehensive and reliable inventory of such warhead motifs available at the time was employed to sift through ChemDiv's stock of compounds [4]. Furthermore, to ascertain their suitability as drug candidates, the structures were subjected to MedChem filters, ensuring their adherence to drug-like characteristics. Our small molecule covalent lysine binders library offers a valuable resource for identifying and designing novel therapeutics with enhanced specificity and potency. By providing access to a curated collection of compounds capable of forming covalent bonds with lysine residues, this library facilitates the rapid screening and optimization of drug candidates targeting a wide range of diseases. It also supports the exploration of new therapeutic targets, accelerating the development of innovative treatments with potentially improved safety profiles and efficacy.

References:

1. Singh, J. (2022). The ascension of targeted covalent inhibitors. Journal of Medicinal Chemistry, 65(8), 5886-5901.

2. Lonsdale, R., & Ward, R. A. (2018). Structure-based design of targeted covalent inhibitors. Chemical Society Reviews, 47(11), 3816-3830.

3. Ishikita, H. (2010). Origin of the pKa shift of the catalytic lysine in acetoacetate decarboxylase. FEBS letters, 584(15), 3464-3468.

4. Abbasov, M. E., Kavanagh, M. E., Ichu, T. A., Lazear, M. R., Tao, Y., Crowley, V. M., ... & Cravatt, B. F. (2021). A proteome-wide atlas of lysine-reactive chemistry. Nature chemistry, 13(11), 1081-1092.