Abstract 6070: Identification of a molecular glue degrader that engages a cancer-specific E3 ligase

Abstract To date, most successful molecular glues have leveraged ubiquitously expressed E3 ligases, most notably Cereblon in the case of the thalidomide derivatives. However, a number of specific E3 ligases are highly over-expressed in certain tumors. Compounds that engage such tumor-specific E3 ligases might provide a unique opportunity to develop molecular glues with higher therapeutic indexes. One such tumor-specific E3 ligase is FBXO5, a member of the F-box family of E3 ligases. Expression analysis suggests this E3 ligase is highly expressed in a wide array of tumor tissues when compared to the corresponding normal tissue, and that within a given tumor type, higher FBXO5 expression correlates with advanced tumor stage and worse disease-free survival. Here, we describe a small molecule (MW~400 Daltons) that uses FBXO5 to function as a molecular glue degrader. This compound, CL-200, exerts cytotoxicity in the nanomolar range across a number of diverse tumor types. The cytotoxicity of CL-200 is abrogated when FBXO5 is knockdown using siRNA. We have further determined that CL-200 induces the FBXO5-dependent proteasomal degradation of at least two critical neosubstrates. One identified neosubstrate is the p150 isoform of ADAR1, an enzyme that catalyzes the posttranscriptional conversion of adenosine to inosine in double-stranded RNA (dsRNA). Evidence suggests that ADAR1p150 is the isoform that confers oncogenic and immune modulating effects in many tumors. Another neosubstrate targeted by CL-200 is c-myc, a critical transcription factor linked to a wide array of tumors. Of note, both p150 ADAR1 or c-myc have been viewed as difficult-to-drug if not undruggable targets. As such, these data suggests that CL-200 functions as a novel molecular glue degrader that engages the cancer-specific E3 ligase FBXO5 to degrade both p150 ADAR1 and c-myc. Structural alteration of CL-200 suggest that chemical modifications can be made that retain the engagement with FBXO5 while altering the neosubstrate profile. Together, these results demonstrate the possibility of leveraging cancer-specific E3 ligases to develop novel molecular glues. Citation Format: Yuan Liu, Mads Larsen, Bo Lin, Irene A. Cardenal, Jason R. Kennerdell, Toren Finkel, Bill B. Chen. Identification of a molecular glue degrader that engages a cancer-specific E3 ligase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6070.