molecules of the month

Compound 6 (BTK)

epoxide-based covalent BTK inhibitor

cysteine reactive, Kinact/Ki ~ 6500

from covalent DEL library screening

Bioorg. & Med. Chem. Lett., May 19, 2021

X-Chem Inc., Waltham, MA

1 min read

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!

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