GNE-0011 / Roche - LARVOL DELTA

Serendipity or design? Concepts and examples of monovalent degraders (ACS-Sp 2024) - "Other examples of monovalent degraders (e.g. GNE-0011, a monovalent BRD4 degrader) have emerged over the last 5 years, often discovered through serendipitous observations. We will discuss concepts and examples of monovalent degraders."

Targeted Protein Degradation • BRD4 • ER

Template-assisted covalent modification of DCAF16 enables BRD4 molecular glue degraders (AACR 2023) - "Molecular glue degraders have emerged as a powerful class of small-molecule therapeutics, as demonstrated by the clinical successes of thalidomide analogs in the treatment of hematological malignancies...In this study, we identified a new class of BRD4 covalent molecular glue degraders (GNE-0011, TMX-4137, MMH-252, MMH-272) by derivatizing electrophiles on the solvent-facing side of a non-degradative BRD4 inhibitor, JQ1...The templated reactivity is likely to exist in other covalent small molecules that engage complementary protein interfaces, and this trans-labeling mechanism can be exploited to develop covalent drugs with more precisely controlled reactivity. Moreover, our findings demonstrate that the decoration of solvent-exposed electrophiles to protein-binding small molecules has great potential to enable discovery and optimization of novel molecular glue degraders."

Hematological Malignancies • Oncology • BRD4 • DDB1