The synthesis and characterization of potential covalent probes for chronic lymphocytic leukemic B‐cell receptors using sulfonyl fluoride

Chronic lymphocytic leukemia is a cancer of the B‐cells. Patients afflicted can become monoclonal for a single B‐cell population and become immuno‐compromised. Current treatments focus on the ablation of all B‐cells without discrimination between healthy and cancerous cells. Following destruction of the immune cells, the patient's immune system is expected to begin producing healthy, non‐cancerous B‐cells again. This is often not the case though and cancerous B‐cell lines often reemerge. A more specific treatment protocol is needed for chronic treatment of patients. The discovery of small molecule, non‐covalent ligands for cancerous B‐cell receptors has been previously reported by the Kodadek lab, but fast off‐rates contributed to challenges in reproducing protein binding success in whole cell systems. The introduction of a sulfonyl fluoride warhead to established non‐covalent probes was performed with the intention of producing selective, covalent probes for cancerous B‐cell receptors. Non‐covalent binding assays by biolayer interferometry confirmed binding to cancerous B‐cell targets. Additionally, incubation of probes with soluble cancerous B‐cell receptor proteins and subsequent trypsin digest and MALDI mass spectrometry analysis seemed to confirm covalent bond formation. Further experiments are ongoing to confirm and characterize this covalent bond formation. Should these probes prove selective for cancerous B‐cell receptors, subsequent attachment to a toxic payload or incorporation into antibody‐drug conjugates could be carried out and tested for efficacy for the selective killing of cancerous B‐cell lines over their healthy counterparts.