Identification of an STING inhibitor targeting the allosteric transmembrane domains

Chen et al. introduce Y-320, a potent allosteric STING inhibitor that uniquely binds to the transmembrane domain instead of the canonical binding pocket, thereby blocking STING activation and traffick...

cell.com

Revolution Medicines' pancreatic cancer drug doubles survival time in Phase 3

Revolution Medicines reported that its experimental KRAS inhibitor, called daraxonrasib, succeeded in a registrational trial for pancreatic cancer.

endpoints.news

Structural optimization of drug molecules with incrementally trained language models - Nature Communications

Machine learning–driven optimization of drug candidates remains a central challenge in medicinal chemistry, particularly when attempting to improve potency without relying on external scoring function...

ino.to

Massive barcode-free chemical screenings enable the discovery of bioactive macrocycles with passive membrane permeability - Nature Communications

Synthetic macrocycles are promising therapeutics; however, most high-throughput discovery platforms rely on genetically encoded libraries of large peptide macrocycles, which are typically not optimized for drug-like properties. Here, the authors report CycloSEL (Cyclic Self-Encoded Libraries), an end-to-end workflow that screens synthetic macrocycle libraries enriched in drug-like ‘beyond rule of five’ features, based on affinity selections and hit identification by tandem mass spectrometry.

ino.to

Roche takes 'leap of faith' with $20M bet on C4T’s antibody-targeted protein degraders

Roche has joined its Big Pharma peers in the emerging degrader-antibody conjugate (DAC) space, paying C4 Therapeutics $20 million upfront and committing more than $1 billion in milestones | Roche has joined Big Pharma peers in the emerging degrader-antibody conjugate space, paying C4 Therapeutics $20 million upfront and committing more than $1 billion in milestones to partner on two oncology targets.

ino.to

Evaluation of Oral PROTAC Guidelines: Efflux Ratio Outweighs Chameleonicity Descriptors

Oral bioavailability of PROTACs, which often fall outside the Rule-of-Five space, is still not perfectly understood. Thus, the design of orally bioavailable PROTACs remains challenging. Chameleonicity...

ino.to

Click. Screen. Degrade. A Miniaturized D2B Workflow for Rapid PROTAC Discovery

Targeted protein degradation is one of the fastest developing fields in medicinal chemistry and chemical biology. Despite significant development in assay technologies and inhibitor discovery, the dev...

doi.org

mRNA Vaccines: What's the Adjuvant?

science.org

Deciphering phosphorylation TACtics: Advances in phosphorylation targeting strategies and bifunctional modalities

Ke et al. review emerging proximity-inducing modalities—phosphorylation-targeting chimera, including PhosTACs, DEPTACs, PhoRCs, and PHICS—that modulate protein phosphorylation via an “event-driven” me...

cell.com

Induced ubiquitination of the partially disordered Estrogen Receptor alpha protein via a 14-3-3-directed molecular glue-based PROTAC design

Proteins lacking defined ligandable pockets remain challenging drug targets. Here, we develop a molecular glue-based PROTAC (MGPROTACs) approach that chemically conjugates a molecular glue stabilizer ...

biorxiv.org

What Do Oral Drugs Really Look Like? Dose Regimen, Pharmacokinetics, and Safety of Recently Approved Small-Molecule Oral Drugs

An analysis of dose, dose frequency, human pharmacokinetics, and potential drug–drug interactions (DDI) was performed on small-molecule oral drugs approved by the FDA from 2020 to 2024 (n = 104). Alth...

pubs.acs.org

Rethinking Ligand Efficiency: Normalization Pitfalls, Uncertainty, and State-Invariant Metrics

Ligand efficiency (LE), defined as the negative binding free energy per heavy atom, is a widely used metric in medicinal chemistry. Yet its mathematical construction embeds a strong size bias that distorts cross-size comparisons, and size-independent variants inherit sensitivity to the arbitrary choice of standard state. This study reviews normalization pitfalls, addresses uncertainty propagation, and introduces a state-invariant, size-normalized metric for efficiency-guided optimization from fragments to leads.

pubs.acs.org

Flagship bets again on AI with Expedition

The prolific company creator is staking $50 million on AI drug discovery for cancer and immune diseases, launching a biotech that already has a partnership with Pfizer.

biopharmadive.com

Twenty Years In Early Stage Biotech VC (Part 3): Business - LifeSciVC

At the end of the day, biotech venture capital is a business and driving returns is the ultimate metric. For twenty years, to deliver on that, I’ve embraced what I call the “first principle” of early ...

lifescivc.com

Twenty Years In Early Stage Biotech VC (Part 2): People - LifeSciVC

Talented people make the magic happen in biotech.  This is the second post in my “Twenty Years In Early Stage Venture” trifecta. Yesterday’s was on Science. Today we’re talking about the People part o...

lifescivc.com

Twenty Years In Early Stage Biotech VC (Part 1) - LifeSciVC

In the blink of an eye, twenty years have passed: in mid-October 2005, I joined Atlas Venture as a principal on the global life science team.  We closed Fund VII a few months after I joined; and, just...

lifescivc.com

RBM39 degrader invigorates innate immunity to eradicate neuroblastoma despite cancer cell plasticity - Nature Communications

Cell state plasticity of neuroblastoma cells is linked to therapy resistance. Here, the authors develop a transcriptomic and epigenetic map of indisulam (RBM39 degrader) resistant neuroblastoma, demon...

doi.org

Confessions of an Ex-Anti-Vaxxer - Macleans.ca

I spent years spouting conspiracy theories about vaccines. Now, as measles rages in my home of Alberta, I’m trying to convince vax-hesitant parents to inoculate their kids.

macleans.ca

An Underappreciated Fate of Drugs in Vivo

science.org

Which halogen to choose? Comparing the effects of chlorine and fluorine as bioisosteric substituents in drug design

The effects of fluorine and chlorine on pharmaceutical systems are compared using a Molecular Matched Pair Analysis. Effects on binding constants, physicochemical properties such as lipophilicity and...

doi.org

Data-driven Design of PROTAC Linkers to Improve PROTAC Cell Membrane Permeability

Proteolysis-targeting chimeras (PROTACs) are promising next-generation therapeutics for the degradation of disease-associated proteins. However, optimizing the physicochemical properties of PROTACs, p...

doi.org

Selectivity Profiling of Bromodomain PROTACs Using Chemical Inducers of Proximity DNA-Encoded Library Screening

Chemical Inducers of Proximity DNA-Encoded Library (CIP-DEL) screening enables high-throughput discovery of compounds that induce protein–protein interactions, including Proteolysis-Targeting Chimeras...

doi.org

RFK Jr. in interview with Scripps News: ‘Trusting the experts is not science’

HHS Secretary RFK Jr. sat down with Scripps News for a wide-ranging interview, discussing mRNA vaccine funding policy changes and a recent shooting at the Centers for Disease Control and Prevention.

scrippsnews.com

Rewiring DNA repair with PARP-based chemical inducers of proximity

Chemical inducers of proximity (CIPs) can elicit durable, and often neomorphic, biological effects through the formation of a ternary complex, even at low equilibrium occupancy of their targets. This ...

biorxiv.org

The CryoEM Structure of Human GPR75: Insights into ECL2-Mediated Activation

GPR75 is one of the most promising emerging targets for the treatment of obesity and related co-morbidities, as its loss of function directly correlates with a decreased body mass index (BMI) in human...

doi.org

Desulfinative Cross-Coupling as a Method to Overcome Problematic Suzuki–Miyaura Reactions of Pharmaceutically Relevant Heteroaromatic Boronates

The well documented difficulties associated with direct (hetero)arylation of aza-aromatics (e.g., azines) at the α-position to nitrogen led to a collaborative project between the Willis group at Oxfor...

pubs.acs.org

Thinking About Covalent Drug Reactivity

science.org

Direct-to-Biology Enabled Molecular Glue Discovery

Molecular glues powerfully control protein proximity but have largely eluded direct screening. A promising avenue for addressing this challenge lies within pinpointing the fundamental features for fun...

chemrxiv.org

Site-resolved assessment of targeted protein degradation

Moreno Ballesteros et al. introduce a site-resolved strategy combining genetic code expansion and bioorthogonal chemistry to evaluate how ligand binding sites influence targeted protein degradation. This approach offers a powerful framework to accelerate degrader design, enable target validation, and broadly explore the potential of induced proximity.

dlvr.it