Small molecule degraders, often referred to as molecular glues, offer the tantalizing prospect of targeting currently undruggable oncoproteins such as transcription factors and chimeric fusion oncoproteins for degradation. Immunomodulatory drugs (IMiDs) are clinically validated molecular glues that bind to Cereblon (CRBN, a substrate receptor of CRL4 E3 ligase) and orchestrate the ubiquitination and subsequent degradation of neosubstrates. We hypothesized that a structurally diverse small molecule library of CRBN modulators would be a valuable research tool to unlock the drug discovery potential of small molecule degraders. Here, we describe the design, synthesis and screening of such library against a panel of cancer cell lines. These efforts led to the discovery of SJ6986, a structurally novel small molecule degrader of G1 to S phase transition 1/2 (GSPT1/2) proteins. The compound showed high degradation efficacy (GSPT1 DC50 = 9.7 nM), potent antiproliferative activity (MV4-11 EC50 = 1.5 nM) and selectivity over 7,000 proteins, as shown by unbiased quantitative TMT-MS proteomics. We further characterized the compound with respect to its ADME and in-vivo properties (F = 87% in mouse). Together, this study demonstrates the utility of a diverse library of CRBN binders in the pursuit of targeting oncoproteins for degradation.

Identification and characterization of potent, selective and orally bioavailable GSPT1/2 degraders from a focused library of Cereblon modulators

ACS Spring Meeting 2021

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