Examination of Coligands in Mefloquine–Metal Complexes Reveals the Structural Determinants of Activity against Plasmodium falciparum and Schistosoma mansoni Mefloquine (MQ) is an important component for antiparasitic therapy. Herein, the synthesis and antiplasmodial and antischistosomal activities of MQ–metal complexes of the general formula [M(II)(L)(MQ)]PF6 are described. Variation of the metal center (platinum and palladium) and coligand (phosphine or bipyridine) consistently yielded MQ coordinated as a N,O-bidentate ligand. Biological evaluation against Plasmodium falciparum and Schistosoma mansoni revealed that the metal center augmented the antiparasitic property of MQ by functioning as a thioredoxin/glutathione reductase-targeting moiety, while the coligand modulated chemical reactivity and physicochemical properties. MQ–Pt complexes displayed high in vivo efficacy. The intracellular accumulation of the metal in parasite cells contributed to the abrogation of essential biochemical pathways. Notably, despite being isostructural, Pd complexes differed from their Pt counterparts in their ligand dissociation behavior. The current work establishes a new structural framework for developing metal-based antiparasitic agents capable of selectively targeting essential parasite biochemical pathways while sparing mammalian cells.

📢 Read all about it in #JMedChem: Mefloquine–metal complexes boost antiparasitic power! 🦠 Platinum (Pt) and palladium variants target redox enzymes in P. falciparum and Schistosoma mansoni, with Pt complexes showing in vivo efficacy: pubs.acs.org/doi/10.1021/...

S29, a rationally designed Omeprazole derivative to disrupt SNAIL-p300/CBP, exhibit anti-atherosclerotic effects in Apoe-/- 🐭

S29⏫proteasomal degradation of SNAIL (NOT Slug Zeb1 Twist)

Microscale thermophoresis➡️Kd 360 nM

T1/2 2 h i.v. 5 h oral

#JMedChem 2026
pubs.acs.org/doi/10.1021/...

ARV-825 is the most commonly used PROTAC-based BRD4 degrader. But, it also targets BRD2/3

Here is a highly specific BRD4 degrader BD-9136

In 🐭tumor xenograft 20 mg/kg i.p.
⏬BRD4 in vivo in 3 h
⏬tumor growth over 4 wk

#JMedChem 2023
pubs.acs.org/doi/10.1021/...
pmc.ncbi.nlm.nih.gov/articles/PMC...

Modeling Metabolite Kinetics with a Partial Differential Equation-Based Hepatic Sinusoidal Model and MALDI-Mass Spectrometry Imaging of Verapamil and Its Metabolites A partial differential-equation-based liver model incorporating sinusoidal blood flow, interstitial fluid, cytosol, and lipid partitioning was developed. Reported multi-indicator dilution data were used to parametrize the model, which was interfaced to whole-body compartmental models and was stable for long simulation times. Using intrinsic clearances from the dispersion model with closed boundary conditions, the model reproduces C–t profiles from standard compartmental models. Any property along the sinusoid can be incorporated, including variation in the intrinsic clearance (enzyme zonation). Spatial distribution of verapamil and its metabolites in rat liver was obtained using MALDI-mass spectrometry imaging and was used to evaluate sinusoidal zonation of drug-metabolizing enzymes. Consistent with previous reports, the observed decrease in the sinusoidal verapamil concentration toward the central vein is consistent with increasing intrinsic clearance along the sinusoid. Incorporation of microphysiology and zonation may provide improved predictions of sequential metabolism, drug–drug interactions, and liver toxicities within specific liver anatomical regions.

Modeling Metabolite Kinetics with a Partial Differential Equation-Based Hepatic Sinusoidal Model and MALDI-Mass Spectrometry Imaging of Verapamil and Its Metabolites #JMedChem pubs.acs.org/doi/10.1021/...

Mass Spectrometry Proteomics: A Key to Faster Drug Discovery Mass spectrometry (MS)-based proteomics is a disruptive platform in drug discovery that offers an exhaustive view of the proteome’s complexity. Focusing on bottom-up MS proteomics, this technology ena...

Mass Spectrometry Proteomics: A Key to Faster Drug Discovery #JMedChem pubs.acs.org/doi/10.1021/...

Discovery of CD28-Targeted Small Molecule Inhibitors of T Cell Co-Stimulation Using Affinity Selection-Mass Spectrometry (AS-MS) and Ex Vivo Validation CD28 is a key T cell costimulatory receptor implicated in antitumor immunity and immune-related disorders, yet no small molecule modulators of CD28 have reached clinical development. Here, we report t...

Discovery of CD28-Targeted Small Molecule Inhibitors of T Cell Co-Stimulation Using Affinity Selection-Mass Spectrometry (AS-MS) and Ex Vivo Validation #JMedChem pubs.acs.org/doi/10.1021/...

Make a nomination! The 2026 Philip A. Portoghese Early Career Award for the Advancement of Medicinal Chemistry recognizes two outstanding early career investigators in the field of medicinal chemistry research.

The deadline for nomination is December 1, 2025. Thank you! #ACSMedChemLett #JMedChem

Promise and Challenge of β-Lactone Electrophiles to Target Aspartate 12 of Mutant KRASG12D The clinical success of covalent KRASG12C inhibition prompts further expansion of the concept to target non-cysteine oncogenic mutation sites as in KRASG12D. This endeavor was hampered by the lack of suitable electrophiles for the selective, covalent engagement of aspartate. Thanks to the recent discovery of β-lactone-bearing covalent inhibitors, new opportunities are emerging. Based on X-ray crystallographic insights and quantum chemical calculations, we herein describe the elucidation of structure–activity and -stability correlations to advance such electrophiles for drug discovery. Guided by predictions of transition state barrier heights for the attack of aspartate 12 at the β-lactone electrophile and structure-based design, we generated substituted β-lactones aiming to balance specific reactivity and chemical and metabolic stability. Our optimization strategy is driven by MS-based and cellular covalent target occupancy assays and PD marker analysis, proteome-wide profiling, and synthetic chemistry. With this work, we aim to expand the use of β-lactones as chemoselective electrophiles in medicinal chemistry.

[4/10] In a #JMedChem paper, a @Novartis team led by Drs. Veronika Ehmke & Saskia Brachmann explored the SAR of K-Ras-targeting β-lactones. Through computation & crystallography, they revealed that our G12Di-7 forms a near-transition-state complex with WT K-Ras. pubs.acs.org/doi/10.1021/...

Enhancing Selectivity and Potency of SNAr Covalent Inhibitors of NADPH Oxidase Enzymes Dysregulated reactive oxygen species (ROS) are implicated in various diseases, positioning NADPH oxidase enzymes (NOXs) as attractive therapeutic targets. However, progress in tool compound discovery ...

Sharing our most recent research published in #JMedChem @acsmedi.bsky.social @pubs.acs.org pubs.acs.org/doi/10.1021/...

Computational Hit Finding: An Industry Perspective Computational hit finding, particularly virtual screening, has been a mainstay of drug discovery campaigns for decades, providing a cost-efficient complement to wet experiments. Innovation in this spa...

Really happy to have contributed to this perspective on computational hit finding approaches! Great team work with Steven Jerome, Fredrik Svensson, Carlos Roca Magadán and Marcel de Groot. #jmedchem #cadd #compchem
pubs.acs.org/doi/10.1021/...

🔜
#KRas #JMedChem

Výsledky tohoto výzkumu, publikované v časopise @acs.org #JMedChem, potvrzují účinnost série proléčiv na bázi derivátů itakonové kyseliny.

Existuje navíc vysoká šance, že látky bude možné podávat ve formě tablet a nejen masti.

#jmedchem with @PierreLlompart

Exploring Alternative Zinc-Binding Groups in Histone Deacetylase (HDAC) Inhibitors Uncovers DS-103 as a Potent Ethylhydrazide-Based HDAC Inhibitor with Chemosensitizing Properties In this work, we synthesized a series of peptoid-based histone deacetylase (HDAC) inhibitors with variations in the linker region and zinc-binding groups. All compounds were investigated for their HDAC inhibition, antiplasmodial activity, and cytotoxicity against native and cisplatin-resistant carcinoma cell lines. The ethylhydrazide 20 (DS-103) proved to be the most effective compound in these primary screenings. DS-103 showed nanomolar inhibition of class I HDACs and of HDAC6 (class IIb). To further investigate the binding mode of DS-103, a crystal structure of DS-103 in complex with HDAC6 was obtained, which represents the first reported crystal structure of an alkylhydrazide in complex with an HDAC enzyme. Importantly, DS-103 completely reversed cisplatin resistance in two different platinum-resistant solid cancer cell lines and demonstrated strong synergism with cisplatin. The synergistic anticancer effects are mediated by increased DNA damage and p21 expression, resulting in caspase-mediated apoptosis and cell death.

Excited to share our latest research which is now out in #JMedChem @pubs.acs.org

A huge thank you to my amazing co-authors and collborators! 🚀

pubs.acs.org/doi/10.1021/...

Ascertaining a Structural Basis in Drug Discovery and Development OR SEARCH CITATIONS

New editorial in #JMedChem on “Ascertaining a Structural Basis in Drug Discovery and Development.” @pubs.acs.org @acsmedi.bsky.social

pubs.acs.org/doi/10.1021/...

Synthetic Approaches to the New Drugs Approved during 2023 This review is the next installment of an annual series that discusses the synthetic routes to access 28 small molecule drugs that were approved worldwide in 2023. A brief description of each drug’s mechanism of action, the history of its discovery and development, and the synthetic approaches published in primary or patent literature that were most likely used for clinical studies or development are included. Synthetic chemistry, used to convert complex intermediates to active compounds or build a new drug from basic building block chemicals, is critical to delivery of new drugs and treatments for disease to patients.

#ChemSky cleanser
The annual #JMedChem article on Synthetic Approaches to the New Drugs Approved during 2023 is out now with industry authors from Takeda, Crosswalk, Merck and Pfizer
A great reference for anyone interested in the synthetic chemistry we use in pharma

Female scientist in front of NMR magnet

Sourdough bread

Siberian husky puppy

As an introduction to #bluesky
-I ❤️ big magnets #chemsky #nmrchat
-I just retired from #pfizer after 35+ years
-I am still active in NMR #SMASH @pubs.acs.org #MRC #JMedChem #consulting
-I ❤️ Sourdough! #chemistswhocook
-I ❤️ sled dogs #UglyDogs

Development and Validation of a UHPLC-MS/MS Method for the Simultaneous Quantification of Candesartan and Bisoprolol Together with Other 16 Antihypertensive Drugs in Plasma Samples Antihypertensive pharmacological therapy is often characterized by a coadministration of different classes of drugs. Therefore, analytical methods allowing the simultaneous quantification of many drug...

Development and Validation of a UHPLC-MS/MS Method for the Simultaneous Quantification of Candesartan and Bisoprolol Together with Other 16 Antihypertensive Drugs in Plasma Samples #JMedChem pubs.acs.org/doi/10.1021/...