Read the full paper: Exploring Non‐Covalent Pin1‐PROTACs Insights Into Degradation Efficiency in Multiple Myeloma Cell Line

Tonight's 30 items run from cereblon glues, HDAC3 PROTACs and covalent DEL hits in medchem to sceptical computational reads on docking reproducibility and virtual-screening hits that fail resynthesis. In industry, uniQure's AMT-130 priority review and the ivonescimab combination race lead.

Tonight's digest has 19 items across medchem, pharmacology and industry; computational had no entries. Chemistry runs from FGFR2/4 PROTACs to MCT1 and ALDH1B1 inhibitors, pharmacology from M4 PAM mechanism to CYP metabolism, and the news is led by Lilly's retatrutide head-to-head win and the Takeda/Innovent Claudin 18.2 ADC.

Developing medicine in space could unlock better treatments.

Varda Space Industries has launched the W-7 vehicle to explore the effects of microgravity on cancer drug formulations, potentially revolutionizing treatment methods.

Breakthrough targeted therapies—from KRAS and PROTACs to CAR T—plus ctDNA monitoring and personalized vaccines push earlier detection and smarter cancer treatment.

Proteolysis-targeting chimeras (PROTACs) represent a transformative therapeutic modality, yet the viability of covalent PROTACs remains debated, as irreversible binding seemingly contradicts the catalytic mechanism of action. Here, we develop and characterize PSIRC3, a potent covalent PROTAC for Bruton’s tyrosine kinase (BTK). PSIRC3 induces selective BTK degradation with a sub-nanomolar DC50 of 0.75 nM and a Dmax of 85%, while its non-covalent counterpart is inactive. Such activity requires covalent bond formation with Cys481, as efficacy is abolished against the C481S BTK mutant. PSIRC3 achieves maximum BTK degradation within 30 min, a kinetic profile linked to rapid cell permeation and efficient ternary complex formation. In vivo, a single administration of PSIRC3 leads to substantial BTK degradation in both PBMCs ( > 80%) and splenocytes ( > 50%). Computational modeling, parameterized with our experimental data, reveals that degradation efficacy is governed by a balance between E3 ligase and target affinities: excessively high E3 affinity is detrimental by inducing a hook effect, while higher target affinity is generally beneficial. Our findings provide strong evidence that covalent engagement can drive potent and selective protein degradation, challenging the notion that catalytic turnover is indispensable for PROTAC efficacy, and open avenues for targeting intractable proteins. Protein degraders are thought to require repeated rounds of action, so molecules binding their target irreversibly were considered unsuitable. Here, the authors describe a covalent BTK degrader active at sub-nanomolar doses in cells and show what governs its potency.

New award to recognize outstanding contributions to chemistry

Proteolysis-targeting chimeras (PROTACs) promote targeted protein degradation by inducing a transient ternary complex between a protein of interest and an E3 ubiquitin ligase. Despite the clinical promise of these event-driven therapeutics, defining the conformational landscape and interfacial organization of these complexes remains challenging. Here, we use an integrated native mass spectrometry (nMS) approach combining ion mobility, surface-induced dissociation (SID), and variable-temperature electrospray ionization (vT-ESI) to determine how small-molecule architecture shapes the structural and thermodynamic landscapes of bromodomain-containing protein 4 (BRD4) with the VCB E3 ligase complex. Using a set of PROTACs that differ in targeting ligand identity (JQ1 versus I-BET726) and PEG linker length, ion mobility measurements show that shorter linkers constrain the ternary complex into more extended topologies, whereas longer, more flexible linkers allow dynamic sampling of relaxed, native-like conformations. SID directly probes noncovalent interfaces and shows that JQ1 complexes favor prompt PROTAC ejection, whereas tighter-binding I-BET726 complexes are more likely to retain the PROTAC at the interface. Complementing these kinetically-controlled gas-phase measurements, vT-ESI reveals a monophasic melting transition for a JQ1-mediated complex and a distinct biphasic melting profile for an I-BET726-mediated complex. The gas-phase activation measurements revealed targeting-ligand-driven differences in PROTAC ejection and retention, whereas vT-ESI uncovered distinct temperature-dependent disassembly pathways for the matched-linker-length JQ10L and IBET10L complexes. Together, these complementary techniques show how PROTAC architecture influences ternary-complex conformation, interfacial connectivity, and disassembly.