Foghorn Ends SMARCA2 Collab With Lilly, Cuts Staff By 40 Percent

We describe the identification of selective SMARCA2, VHL-based heterobifunctional degraders. Structurally novel indolo[1,2-a]quinazolin-5(7H)-one SMARCA bromodomain binders were optimized and then con...

In the SWI/SNF chromatin-remodeling complex, the mutually exclusive catalytic ATPase subunits SMARCA2 and SMARCA4 proteins have a synthetic-lethal relationship. Selectively targeting SMARCA2 for degra...

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SMARCA2 is an attractive synthetic lethal target in human cancers with mutated, inactivated SMARCA4. We report herein the discovery of highly potent and selective SMARCA2 PROTAC degraders, as exemplif...

Is SMARCA2 the next KRAS moment for targeted protein degradation? Degraders are stepping in where SM have stalled? 📈 Lauren Martz dives into clinical and PC strategies across Prelude Therapeutics, ...

Foghorn and Lilly will not advance FHD-909 or their SMARCA2 degrader. Foghorn is cutting about 40% of staff to fund its pipeline into late 2029.

Background:. The SWI/SNF chromatin remodeling complex is crucial for normal B cell development. Its importance is underlined by the occurrence of somatic mutations in genes coding for subunits of the ...

The authors identified a series of covalent, monovalent glue degraders that can co-opt two E3 ligases, DCAF16 and FBXO22, in a parallel fashion to degrade SMARCA2/4 and demonstrated that ligase prefer...

The identification of VHL-binding proteolysis targeting chimeras (PROTACs) that potently degrade the BRM protein (also known as SMARCA2) in SW1573 cell-based experiments is described. These molecules ...

Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex, including SMARCA4 in nonsmall cell lung cancer with a frequency of up to 33% in advan...

Proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) target proteins for degradation by co-opting an E3 ligase. While heterotrivalent PROTACs that can recruit multiple E3 ligases have been described, all MGDs reported to date depend on a single E3. Using orthogonal genetic screening, biophysical and structural analyses, we show that a monovalent MGD can recruit CUL4DCAF16 and CRL1FBXO22 in parallel to degrade SMARCA2/4. Deep mutational scanning identifies C173 in DCAF16 as essential for degrader activity and intact protein mass spectrometry confirms covalent modification at this site. Elucidating the ternary complex structure reveals a unique binding mode and a distinct interface of neointeractions that underlie degrader specificity. We demonstrate that ligase dependency is chemically and genetically tunable. Minimal compound modifications shift preference from DCAF16 to FBXO22, while a single substitution boosts degrader dependency on DCAF16. These results esta

Rouhimoghadam et al. demonstrate that single-atom chemical edits can reprogram E3 ligase selection by molecular glue degraders. By revealing that only specific ternary complex geometries drive ubiquitination, this work establishes a mechanistic framework for designing tunable, ligase-switchable degraders.