Design and Synthesis of Novel Cereblon Binders for Use in Targeted Protein Degradation

Modulating the chemical composition
of cereblon (CRBN) binders
is a critical step in the optimization process of protein degraders
that seek to hijack the function of this E3 ligase. Small structural
changes can have profound impacts on the overall profile of these
compounds, including depth of on-target degradation, neosubstrate
degradation selectivity, as well as other drug-like properties. Herein,
we report the design and synthesis of a series of novel CRBN binding
moieties. These CRBN binders were evaluated for CRBN binding and degradation
of common neosubstrates Aiolos and GSPT1. A selection of these binders
was employed for an exploratory matrix of heterobifunctional molecules,
targeting CRBN-mediated degradation of the androgen receptor.