Compound 6 (BTK)
the X-Chem covalent BTK inhibitor, compound 6, is an example of a covalent inhibitor discovered using DNA-encoded library chemistry, and is the first epoxide-based covalent inhibitor discovered against BTK. Screening for novel covalent scaffolds is challenging, and many covalent leads are instead discovered from reversible starting points. This approach applying DNA-encoded library technology to covalent molecule discovery may be useful, especially in identifying non-acrylamide warheads like this example. This paper offers a great case study on how to execute and follow up on such a screen. One eye-catching reagent employed in the screen is “sheared salmon sperm DNA as a general blocking agent.” We’d love to hear from any readers the history behind that one!