Optimization of a Novel DEL Hit That Binds in the Cbl-b SH2 Domain and Blocks Substrate Binding
Jun Liang,
Michael J. Lambrecht,
Teresita L. Arenzana
et al.
Abstract:We were attracted to the therapeutic
potential of inhibiting Casitas
B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING E3 ligase that
plays a critical role in regulating the activation of T cells. However,
given that only protein–protein interactions were involved,
it was unclear whether inhibition by a small molecule would be a viable
approach. After screening an ∼6 billion member DNA-encoded
library (DEL) using activated Cbl-b, we identified compound 1 as a hit for which the cis-isomer (2) was confirmed by… Show more
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