ChemMedChem最新文献

Site-specific antibody-drug conjugates (ADCs) represent a promising class of biotherapeutics with enhanced pharmacological profiles. we herein report a novel one-step strategy for preparing homogeneous ADCs with a drug-to-antibody ratio (DAR) of 4. This approach leverages a Fc ligand-directed thioester-based acylating reagent combined with a β-glutamic acid-based branching linker to enable precise conjugation of four MMAE molecules per antibody. Through systematic optimization of buffer composition and pH, we successfully mitigated the hydrophobicity-driven aggregation typically associated with K248-linked DAR4 ADCs, while maintaining exceptional conjugation efficiency. The method demonstrates excellent tolerance to protein concentration and is applicable to multiple IgG subtypes, including those targeting HER2, cMet, ROR1, and FRα. All resulting ADC products exhibited high homogeneity. Notably, ADC-4, functionalized with a VK(SO₃H)-modified linker, showed enhanced aggregation stability, potent tumor suppression, and a favorable safety profile, highlighting its promising therapeutic potential.

The cover art illustrates a polydopamine (PDA)-based nanoparticle system loaded with the photosensitizer chlorin e6 (Ce6) and paramagnetic manganese oxide (MnO), designed for precise imaging and treatment of breast cancer. Nezha, wielding a fire-tipped spear, symbolizes the photothermal and photodynamic effects, while the dragon's water-spraying attack represents the MnO-driven oxidative cascade. Both Nezha (fire sphere) and the dragon (water sphere) originate from the core sphere (MnO/Ce6@PDA@CCM), with the villain symbolizing breast cancer. Further details can be found in the Research Article by Wei Zhang and co-workers (DOI: 10.1002/cmdc.202500617).

ABCG2-mediated multidrug resistance (MDR) is a major challenge among chemotherapeutic treatments of colon, pancreatic, and breast cancer, as well as leukemia. Clinical oncology seeks new adjuvant therapeutics to overcome MDR by developing potent but nontoxic ABCG2 inhibitors. Aided by computational docking analyses, based on known substrate and inhibitor structural motifs, a new isoquinolinone framework and several (poly)methoxylated derivatives were designed and synthesized. The novel carborane-containing N-carboranyl isoquinolinones were evaluated for cytotoxicity, ABCG2 inhibition, and reversal of MDR in combination with mitoxantrone (MXN) in an ABCG2-expressing Madin–Darby canine kidney II cell model. While the parental compound IC-1 showed strong ABCG2 inhibition, its 4-methoxyphenyl, 3,4-dimethoxyphenyl, and 3,4,5-trimethoxyphenyl derivatives (IC-4, IC-5, and IC-6) exhibited improved ABCG2 affinity. Nonsubstituted isoquinolinones IC-1 to IC-6 displayed higher solubility, lower toxicity, and similar ABCG2 inhibition and reversal of MXN resistance than 6,7-dimethoxy-isoquinolinone derivatives IC-7 to IC-11. Especially, the 4-methoxyphenyl- and 3,4-dimethoxyphenyl-substituted isoquinolinones (IC-10, IC-11) caused the strongest left shift of the MXN IC₅₀ value by 8.1- and 7.2-fold, indicating effective resensitization to the chemotherapeutic agent. Therefore, carborane-containing isoquinolinones featuring additional methoxy groups represent a promising approach for the development of ABCG2 inhibitors to overcome resistance to anticancer drugs.

The paradigm of targeted therapy has been revolutionized by the development of proximity-inducing chimeras, particularly proteolysis-targeting chimeras (PROTACs), which offer a therapeutic strategy for previously “undruggable” targets. However, the degradation of certain essential proteins can lead to off-target toxicity, prompting the development of nondegradative proximity-inducing chimeras. This review categorizes current nondegradative chimeras into several functional classes, including targeted inhibition, targeted stabilization, post-translational modification (PTM), and cellular switches; elaborates on the mechanisms of action for each category; and introduces representative technologies, including molecular glues (MGs). Furthermore, the review highlights cutting-edge research and recent advancements in the field. Unlike previous reviews focusing primarily on degradative chimera technologies, this article systematically categorizes nondegradative modalities into inhibition, stabilization, PTM, and cellular switches, providing a unified mechanistic framework and highlighting emerging therapeutic applications beyond oncology.

A series of adamantane-based amino acid derivatives incorporating γ-aminobutyric acid (GABA) as a spacer, with the general structure Ad-CH₂-CO-GABA-X-OMe (where X represents L-tryptophan (Trp), L-histidine (His), H-Ala-((S)-2-oxopyrrolidin-3-yl)-OMe (Pld), or L-methionine (Met)), were synthesized and evaluated in vitro for their antiviral activity against rimantadine-resistant influenza A virus strains A/Moscow/78/2020(H1N1)pdm09 and A/Cheboksary/125/2020(H1N1)pdm09. The results demonstrated that the presence of an L-tryptophan residue is crucial for effective inhibition of influenza virus replication, with the corresponding derivative exhibiting potent activity at an IC50 of 0.5 µg/mL. A comparative analysis of structural features and antiviral properties was conducted between the adamantane derivatives and analogous derivatives of the closo-decaborate anion ([B₁₀H₁₀]^2–) functionalized with identical amino acid residues Na₂[B₁₀H₉–O(CH₂)₂O(CH₂)₃C(O)–X–OCH₃] (X = Trp, His) and spacers of comparable length. This study suggests that combining adamantane-based compounds with closo-decaborate clusters could lead to the development of highly effective therapeutic compositions with enhanced efficacy and improved safety profiles.

We report the design, synthesis, and biological characterization of a pseudo-NP (PNP) collection inspired by the mesembrine alkaloid scaffold. A scalable, microwave-assisted intramolecular Diels–Alder furan cyclization enabled efficient access to the 3a-aryloctahydroindole (AOHI) core, which served as a versatile intermediate for diversification through NP-fragment fusion. The resulting AOHI-based PNPs explore chemical space bridging properties of NPs and drug-like molecules. Morphological and bioenergetic profiling revealed distinct mitochondrial phenotypes, including altered morphological features and respiration consistent with complex I perturbation. These findings highlight the AOHI scaffold as a versatile and synthetically accessible alkaloid-derived fragment for PNP design and as a valuable source for novel biologically active compound classes.

Depicted on the cover is the discovery of a collapsed S1 pocket conformation in Factor VIIa induced by an oxazole based inhibitor. The magnified view shows how ligand binding remodels the active site and displaces the 215–217 loop, creating an inactive conformation. Supported by extensive molecular dynamics simulations, this work demonstrates that such collapsed states occur spontaneously in many serine proteases. These insights establish S1 pocket plasticity as a general mechanistic feature and open new avenues for inhibitor design. Stefan Güssregen, Herman Schreuder, Gerhard Hummer, and co-workers (DOI: 10.1002/cmdc.202500846). The background was created with BioRender.com.

Antitumor efficacy based on conventional chemodynamic therapy (CDT) is frequently constrained by insufficient endogenous H₂O₂ and the limitations of monotherapy. Herein, we developed a metal-organic nanoplatform (CA-Fe NPs). This platform was fabricated through Fe³⁺-driven coordination assembly of artesunate (AS) and chlorin e6 (Ce6), facilitating preferential tumor accumulation via the enhanced permeability and retention (EPR) effect. Upon cellular internalization and 660 nm laser irradiation, the nanodrug enables a synergistic combination of Ce6-mediated photodynamic therapy (PDT) and AS-induced oxidative stress, which collaboratively amplifies intracellular reactive oxygen species (ROS) generation. This cascade induces mitochondrial membrane potential collapse, leading to extensive apoptotic cell death (77.5%). In a 4T1 tumor-bearing mouse model, this approach achieved marked tumor suppression with an excellent safety profile, offering a promising strategy for combination 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.

The Farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that represents an important therapeutic target for gut-liver diseases and metabolic disorders. Recently, FXR partial agonists have gained attention for their potential to minimize side effects resulting from receptor over-activation. In this study, we report the design, synthesis, and biological evaluation of novel obeticholic acid (OCA) derivatives as selective FXR modulators. Structural modifications at the C3α position and the side chain of the bile acid scaffold led to the identification of valine derivatives 2 and 16 as metabolically stable and safe FXR modulators with reduced agonist efficacy. Further molecular dynamics simulations revealed that these compounds induce distinct conformational changes within the FXR ligand-binding domain, consistent with their partial agonist behavior and resulting in moderate modulation of FXR target genes. Unlike OCA, both compounds failed to activate other steroid-responsive receptors, including MRGPRX4 (hX4), a G-protein-coupled receptor implicated in itching in cholestatic patients, supporting their potential as safer FXR modulators with a reduced risk of pruritus-related side effects. Overall, this study elucidates key structure–activity relationships governing FXR partial agonism and hX4 binding and offers valuable chemical tools for the development of FXR-targeted therapeutics with improved safety profiles.