Adam Gilbert

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...

How SAR should be explored on heterobifunctional platforms

doi.org/10.1021/acs....

mRNA Vaccines: What's the Adjuvant?

Good one today from @dereklowe.bsky.social

mRNA Vaccines: What's the Adjuvant? | Science | AAAS www.science.org/content/blog...

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...

Good summary of the induced proximity phosphorylation space; still waiting for this to be reduced to practice for therapeutic value in the clinic.....

www.cell.com/cell-chemica...

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 ...

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

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...

Fantastic resource from Dean Brown....

What Do Oral Drugs Really Look Like? Dose Regimen, Pharmacokinetics, and Safety of Recently Approved Small-Molecule Oral Drugs | Journal of Medicinal Chemistry pubs.acs.org/doi/10.1021/...

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.

More thoughts on LE....

Rethinking Ligand Efficiency: Normalization Pitfalls, Uncertainty, and State-Invariant Metrics | ACS Medicinal Chemistry Letters pubs.acs.org/doi/10.1021/...

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.

www.biopharmadive.com/news/flagshi...

And Part 3....

lifescivc.com/2025/10/twen...

Part 2....

lifescivc.com/2025/10/twen...

A very good read...

lifescivc.com/2025/10/twen...

A lot going on in that brain of yours Keith 😀. I've never been a huge of fan of the term but to me it's more of - you know it when you see it in someone - it's hard to define....

Pretty interesting I/O result in neuroblastoma using indisulam

Singh, S., Fang, J., Jin, H. et al. RBM39 degrader invigorates innate immunity to eradicate neuroblastoma despite cancer cell plasticity. Nat Commun 16, 8287 (2025). doi.org/10.1038/s414...

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.

"The anti-vax movement isn’t simply a grassroots network of concerned parents. It’s an industry. It’s lucrative, selling supplements, e-books, courses and products." macleans.ca/longforms/co...

Both will be/should be used - they have different effects in molecules depending on how they are used....

An Underappreciated Fate of Drugs in Vivo

An Underappreciated Fate of Drugs in Vivo | Science | AAAS www.science.org/content/blog...

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...

Which halogen to choose? Comparing the effects of chlorine and fluorine as bioisosteric substituents in drug design | ChemRxiv - doi.org/10.26434/che...

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...

Data-driven Design of PROTAC Linkers to Improve PROTAC Cell Membrane Permeability | ChemRxiv - doi.org/10.26434/che...

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...

BD1/BD2 selectivity exploration across BRDs using CIP-DELs
doi.org/10.1021/acsc...

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.

1. "'Trusting the experts is not a feature of either a science or democracy," Kennedy said."

It's literally a vital feature of both science and of representative democracy.

I've written a fair bit about trust in expertise as a vital mechanism in the collective epistemology of science.

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 ...

PARP/BRD4 CIPs which could potentially treat PARP resistant tumors

www.biorxiv.org/content/10.1...

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...

High profile obesity target structure solved with implications for activation

doi.org/10.1101/2025...

I'm a big fan of The Basher as well. Will now put on my Rockpile playlist for the rest of the day....

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...

Important paper given the plethora of heteroaryl moieties in clinical assets

Desulfinative Cross-Coupling as a Method to Overcome Problematic Suzuki–Miyaura Reactions of Pharmaceutically Relevant Heteroaromatic Boronates | ACS Medicinal Chemistry Letters pubs.acs.org/doi/10.1021/...

Thinking About Covalent Drug Reactivity

Derek's very good explanation of the excellent recent Srinivasan covalent inhibition kinact/KI optimization paper...

Thinking About Covalent Drug Reactivity | Science | AAAS www.science.org/content/blog...

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...

Direct to Biology/ASMS molecule glue screening platform. Should be enabling for small molecule induced proximity investigations...

chemrxiv.org/engage/chemr...

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.

Online now! #chembiol

Sortilin mediated extracellular degradation

patentscope.wipo.int/search/en/de...

This is pretty slick - SMARCA2 phosphate prodrug PROTACs which achieve high exposure in the gut but low systemic exposure when dosed PO

patentscope.wipo.int/search/en/de...

RIPTACs for Precision Cancer Therapy: A Novel Modality with the Inspiration of HLD-0915 as the First Candidate in Clinical Trials

Good summary describing HLD-0915 and RIPTACs

doi.org/10.1021/acs....

One of the true musical geniuses. Pet Sounds still blow me away....