ChemMedChem最新文献

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.

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.

Polydopamine (PDA)-based nanoparticles demonstrate significant potential for breast cancer photodynamic therapy and photothermal therapy, owing to their nanoscale dimensions and superior biocompatibility. However, their efficacy is limited by the tumor microenvironment and shallow near-infrared (NIR) laser penetration. In this study, we developed a novel nanoparticle system, MnO/Ce6@PDA, with a PDA core loaded with photosensitizer chlorin e6 (Ce6) and coated with manganese oxide (MnO) for synergistic PTT/PDT. Utilizing the photoresponsive properties of PDA and Ce6, along with the oxidative capacity of MnO, the nanoparticles demonstrated strong photothermal conversion and catalytic activity. Coating with tumor cell membrane (MnO/Ce6@PDA@CCM) preserved adhesion proteins such as integrins and cadherins, enabling homotypic targeting and tumor-specific accumulation. Under NIR laser irradiation at different wavelengths, the nanoparticles generate significant amounts of reactive oxygen species and singlet oxygen, resulting in the death of tumor cells via mitochondrial and cell membrane damage. The release of Mn²⁺ ions during tumor microenvironment-responsive degradation not only enhanced T1-weighted magnetic resonance contrast, but also potentiated chemodynamic therapy via Fenton-like reactions, enabling real-time imaging-guided combinatorial antitumor efficacy.

Molecular blocks (MBs) offer a drug-free approach to cancer therapy by utilizing polymeric nanoparticles that remain dispersed in the bloodstream but aggregate within the acidic tumor microenvironment (pH 6.3-6.5) to disrupt cancer cell membranes. Herein, a pH-responsive polymeric MB is developed by conjugating deoxycholic acid (DCA) to chitosan (CS) through a water-based modification using CS succinate (CS-S). The resulting CS-S-DCA nanoparticles exhibit significant aggregation at pH 6.2 while maintaining a smaller size at physiological pH (7.4), demonstrating pH-triggered behavior. This leads to selective cytotoxicity against cancer cell lines (MiaPaCa-2, A-549, and HT-29) while preserving compatibility with normal human dermal fibroblasts. Fluorescence imaging confirms preferential adhesion of CS-S-DCA to cancer cells over normal cells. Encouraged by these findings, in vivo studies in a mouse model are conducted, which reveal significant tumor suppression without the use of conventional drugs. This work highlights the potential of concerted pH-responsive polymeric MBs as a promising and biocompatible strategy for drug-free cancer therapy.

Antibody-based drugs targeting the PD-1/PD-L1 axis have become widely used in clinical treatments. However, challenges such as high costs and suboptimal clinical response rates have fueled growing interest in developing small-molecule inhibitors. Recent clinical trials, both domestically and internationally, have evaluated several small-molecule inhibitors. Notable compounds like CA-170 and INCB086550 have shown promising properties and potential in these studies. Although no small-molecule inhibitors targeting PD-L1 have yet been approved for clinical use, the path to their development and clinical translation is fraught with challenges. Researchers are actively exploring innovative strategies for drug design and synthesis, while carefully assessing critical factors such as safety and efficacy. Given the essential role of the PD-1/PD-L1 pathway in immune evasion by tumors, this review provides a concise overview of the signaling and structure of PD-1/PD-L1, summarizes current progress on clinical candidate drugs targeting this pathway, discusses the challenges in translating small-molecule inhibitors to clinical practice, and outlines future directions in drug development.

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.

Human elastase 1 has been shown to possess an important role in maintaining skin stability and elasticity through the proteolytic cleavage of elastin (ELN), a hydrophobic protein that serves as a key component of extracellular matrix in the skin. The development of antielastase agents represents a promising therapeutic approach for treating skin pathologies characterized by elastin degradation, with applications in both dermatology and cosmetology. Reversible inhibitors represent a therapeutic strategy, offering selective inhibition of elastase proteolytic activity while preserving the function of other physiologically essential serine proteases. Using porcine pancreatic elastase (PPE) as a well-established surrogate of human skin elastase, a focused series of noncovalent inhibitors designed to bind the catalytic area of PPE is assayed. Several compounds display an antielastase activity, including N-(2-bromophenyl)-2-(6-chloro-1-(3,5-dimethylbenzyl)-1H-benzo[d]imidazol-2-ylthio)acetamide (7) that exhibits the most potent inhibitory effects (IC₅₀ = 41.1 µM), similar to standard compound oleanolic acid (IC₅₀ value of 25.7 µM). The observed structure-activity relationship is further validated through molecular docking and dynamic studies, which provide mechanistic understanding of the binding interactions and establish suggestions for further rational drug design.

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).