ChemMedChem最新文献

This cover shows the quinazolinone 4k approaching 26S proteasome, as discovered by limited proteolysis-based functional proteomics. Its interacting partners, the 20S β2 and β5 subunits, are depicted in white and light blue, respectively. The resulting inhibition of β5 chymotrypsin-like activity results in 4k cytotoxicity, represented by the green living cells turning into red, dying ones. More details can be found in the Research Article by Carmen Festa, Maria Chiara Monti, and co-workers (DOI: 10.1002/cmdc.202500728).

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor whose activation promotes phagocytosis and neuroprotection in Alzheimer's disease (AD) and related neurodegenerative disorders. While therapeutic efforts have largely focused on antibodies, small-molecule TREM2 modulators remain limited. Here, we applied a structure-based virtual screening workflow targeting a putative allosteric site on TREM2, guided by PyRod-derived pharmacophores from molecular dynamics simulations. Screening of the Enamine Collection (ESC) yielded 20 candidate compounds, three of which demonstrated binding in TRIC assays. The top hit, EN020, exhibited a K_D of 14.2 µM (MST) and 35.9 µM (SPR), and significantly enhanced microglial phagocytosis in BV2 cells, outperforming the known TREM2 agonist VG-3927. A preliminary structure–activity relationship (SAR) study, including synthetic and catalog-derived analogs, highlighted a narrow tolerance for scaffold modifications, with only T2V002 retaining partial TREM2 binding affinity. This work identifies EN020 as a novel small-molecule TREM2 modulator with functional activity, providing a framework for rational optimization toward potential AD therapeutics.

Magnetic nanoparticles (MNPs) have emerged as a promising tool for cancer therapy, providing significant potential for multimodal cancer treatments that include chemotherapy, magnetic hyperthermia, and bioactive targeting. The physicochemical properties of MNPs, including size, surface chemistry, and magnetic properties, play a crucial role in determining their therapeutic effectiveness and overall performance in multimodal cancer therapy. The present study introduces a magnetic nanoformulation (cMNP-mPEG-Dox-Ab) nanobioengineered for an integrated therapeutic approach. The cubic-shaped MNPs (cMNP) are functionalized with a biocompatible polymer, mPEG-NH₂, to immobilize anti-HER2 antibody and the anticancer drug doxorubicin. The nanoformulation exhibits a controlled drug release in response to pH and temperature stimuli. Notably, under an alternating magnetic field (AMF), 64% drug release is observed at an acidic pH, which mimics the tumor microenvironment. Cytotoxicity studies on the HCC1954 breast cancer cells reveal that the nanoformulation without an anti-HER2 antibody induces 25% cell death, which increases to 52% upon conjugation with the anti-HER2 antibody, confirming the bioactive targeting effect. Apoptosis studies demonstrate a significant increase in the apoptotic cell population under hyperthermic conditions relative to the physiological temperature. This study underscores the potential of cMNP-mPEG-Dox-Ab nanoformulation to enhance the precision and therapeutic efficacy of multimodal cancer therapy through bioactive targeting.

Quinazolinones have been recently recognized as valuable scaffolds for developing novel therapeutic opportunities. They indeed exhibit structural versatility and a wide range of biological activities, including antifungal, antitubercular, antihypertensive, anticancer, and antiviral ones. In this work, a focused library of new bioactive 4-(3-H)-quinazolinones has been synthesized, their cytotoxic action against DU-145 prostate cancer cells has been detailed, and compound 4k has been revealed as the most active one. Consequently, its interactome has been characterized by a label-free functional proteomics-based platform coupling drug affinity responsive target stability (DARTS) and targeted limited proteolysis-multiple reaction monitoring-mass spectrometry (t-LiP-MRM-MS). This multifaced strategy has been employed to reveal few subunits of the 26S proteasome machinery as the most reliable compound 4k biological targets. This paved the way for the deepening of the protein–ligand interaction using in vitro and in silico bio-orthogonal techniques. Finally, the analysis of its function in living DU-145 cells prompted compound 4k as a novel quinazolinone-bearing inhibitor of the chymotrypsin-like activity of the proteasomal β−5 subunit, stirring this framework for the development of new anticancer drugs.

Modern drug discovery faces high rates of clinical attrition, more challenging therapeutic targets, increasing molecular complexity, and rising research and development costs. These challenges are not only due to greater scientific risk, but also the way that organizations leverage drug discovery knowledge. It is believed that effective knowledge sharing—both tools and culture—is core infrastructure that can increase the probability of success. Readily accessible knowledge hubs built on familiar software (OneNote + SharePoint → “OnePoint”) and enterprise wikis (Pfizerpedia) scale well because information capture happens during daily work, not outside it. Chemistry-focused platforms, such as Roche's system based on brief “knowledge slides,” turn tacit insights into reusable design precedent. At AstraZeneca, a MediaWiki-based Compound Design Database (CDD) tied to quantitative structure–activity relationship (QSAR) models and explicit tracking of the design–make–test–analyze (DMTA) cycle cut idea-to-compound time by 50% through synchronizing design and synthesis. Codifying heuristics (e.g., Drug Guru's 186 rule-encoded transformations) institutionalizes expert playbooks while training newer chemists. Furthermore, it is discussed how the durable impact of knowledge sharing depends on human systems (networks, incentives, curated “push” updates, and embedded workflows), as well as curated external knowledge streams that supply early competitive signals and context for action.

This 2026, ChemMedChem turns 20! Our Anniversary Cover celebrates the traditional and the new. Our signature yellow, reminiscent of our predecessor Italian journal Il Farmaco, represents the journal’s beginnings and core content of traditional medicinal chemistry. The ribbon model of a GPCR represents the future of drug discovery and therapeutics—from computational methods to novel therapeutic modalities. This is all framed by a more abstract, artistic rendering of a protein structure, reminding us that while computational models and AI surround us, human creativity and insight are more important than ever. Like the painting, science can be messy and unexpected, but overall, still a beautiful human endeavor. Finally, two additional colors represent our key partners. Blue-green is for our sister journal ChemBioChem, with whom we work closer than ever before. Dark blue is for the European Federation for Medicinal Chemistry and Chemical Biology (EFMC), for which we serve as an official journal. Watch out for more information about the journal’s history and anniversary activities in upcoming Editorials throughout the year. Cover art by Robert de Angelo A. Bolinas.

Focal adhesion kinase (FAK) has emerged as a promising therapeutic target for cancer owing to its key roles in the development and aggressiveness of tumor malignancy. However, exploring the clinical translation of FAK inhibitors has been recently hindered by their lack of selectivity and specificity for cancer cells. In this study, the synthesis and biological evaluation of a trimeric β-glucuronidase-responsive albumin-binding prodrug programmed for the selective delivery of a potent FAK inhibitor within solid tumors are reported. When activated by β-glucuronidase, a glycosidase overexpressed in the microenvironment of numerous tumors, this prodrug induces a remarkable inhibition of breast cancer cell (MDA-MB-231) growth with an IC₅₀ value of 0.63 ± 0.02 μM. Furthermore, mechanistic studies show that upon enzymatic activation, the prodrug delays cell cycle progression by arresting cells in the G2/M phase. These results indicate that our delivery strategy may be applied as a promising new FAK-targeted therapy for cancer.

Complexes are emerging as promising alternatives for the treatment of neglected parasitic and viral infections, which urgently require new therapeutic strategies due to limited effective drugs. In this study, a series of [Pt(II)(phpy)(PR₃)Cl] complexes, where phpy is 2-phenylpyridine, and PR₃ represents triphenylphosphine (PPh₃), 1,3,5-triaza-7-phosphaadamantane (PTA), para-benzoic acid-diphenylphosphine (PPh₂(Php-COOH), or tris(2-carboxyethyl)phosphine (TCEP), are synthesized and systematically evaluated for their chemical properties and in vitro biological activities. Chemical reactivity, including ligand exchange with L-histidine and N-acetylcysteine, hydrophilic/lipophilic balance, and interactions with bovine serum albumin (BSA) and DNA, was correlated with biological outcomes. The novel TCEP complex exhibited exceptional chloride stability and intrinsic fluorescence but lacked antiviral and antileishmanial activity. The PTA derivative showed selective antileishmanial activity, achieving a selectivity index (SI) of 10.8 and reducing the infectivity index by 40% at 12 µM. Also, PTA showed selective antitumor activity in ovarian cancer (SI 9.1). In contrast, the PPh₂(Php-COOH) derivative demonstrated significant antiviral activity, inhibiting Mayaro virus and Zika virus replication by 94% and 78%, respectively, at 50 µM. These findings underscore the potential of coordination chemistry to fine-tune biological activity and support the rational design of metal-based therapeutics for neglected diseases.

The cover art depicts a novel chemotype of azolopyrimidine-6-carbonitriles as antiproliferative compounds. A fence represents a non-selective compounds that protect sheep (normal HEK-293 cells) against wolves (cancer cells), whereas a shepherd is selective against A-172 cell line and shepherd dog is selective against T-24 cells with CDK2 as plausible target. Two «wolves in sheep’s clothing» represent compounds with cytotoxicity against HEK-293 cells only. The sheep side is purple and wolf side is yellow according to MTT assay colors. More details can be found in the Research Article by Konstantin V. Savateev and co-workers (DOI: 10.1002/cmdc.202500535).