ACS Medicinal Chemistry Letters最新文献

Innovations in pharmaceutical science drive new treatment approaches for cancer and brain injury. This Patent Highlight reviews findings from three patents focused on kinase inhibition in cancer therapy and using biomarkers to assess brain injury. By targeting key enzymes such as AKT1 and diacylglycerol kinase alpha (DGKα), these innovations offer new strategies for cancer treatment, particularly in cases of resistance to conventional therapies. In parallel, advances in biomarker-based diagnostics provide a more sensitive means of detecting traumatic brain injuries (TBI). Together, these breakthroughs hold promise for improving outcomes in oncology and neurology.

This Patent Highlight explores recent innovations in neuroscience and neurotechnology, particularly in brain monitoring and stimulation. It examines four essential patents: novel psychoplastogens for neuronal growth, techniques for transferring emotional states, and advanced systems for self-guided neural diagnostics and treatment. The discussion extends to deep brain stimulation (DBS) for motor and memory disorders, enhanced brain function monitoring through electroencephalography (EEG), and the role of artificial intelligence in personalizing treatment strategies. These advancements represent a pivotal development in neurotechnology, introducing innovative methodologies for elucidating neurological mechanisms, addressing psychiatric disorders, and augmenting cognitive and neural function.

Recent advances in biotechnology have brought novel solutions to both metabolic diseases and sustainable agriculture. This Patent Highlight examines innovation from four recent patents focusing on the genetic modification of microbes for nitrogen and carbon fixation and the development of pharmaceutical compounds to target critical metabolic pathways. These breakthroughs have potential applications in fields ranging from industrial biotechnology and agriculture to cancer therapy and metabolic disease treatment, providing new strategies for addressing global health and environmental challenges.

Linezolid, a widely used oxazolidinone antibiotic, exhibits potent activity against resistant bacterial infections but is associated with serotonergic toxicity, primarily due to its inhibition of monoamine oxidase (MAO). MAOs, consisting of MAO-A and MAO-B isoforms, play crucial roles in neurotransmitter metabolism, with implications for neurodegenerative disorders like Parkinson's and Alzheimer's diseases. This study aims to optimize Linezolid's structure to transform it into a selective MAO-B inhibitor. Utilizing structure-activity and structure-toxicity relationship approaches, novel analogues of Linezolid were synthesized by replacing its oxazolidinone ring with a thiadiazole scaffold. Among the synthesized compounds, 6b emerged as a lead candidate, displaying a remarkable MAO-B inhibitory activity (IC₅₀ = 0.03 μM) and 464-fold selectivity over MAO-A, compared to the standard drugs Pargyline (IC₅₀ = 0.14 μM) and Clorgyline (IC₅₀ = 1.85 μM). Furthermore, docking and molecular dynamics simulations corroborated the high affinity and stability of compound 6b in the MAO-B enzyme's binding pocket. These findings suggest that optimized Linezolid analogues, particularly compound 6b, hold promise as selective MAO-B inhibitors, offering therapeutic potential for treating neurodegenerative diseases while avoiding the risks associated with serotonergic toxicity.

We proposed a novel ligand for the interaction with human serum albumin (HSA) to extend the blood half-life of small molecular weight therapeutics. The ligand features an alkyl chain and an activated disulfide to allow binding to the hydrophobic pockets of HSA and the formation of disulfide to Cys34 of HSA, thereby minimizing the initial renal clearance. The dual nature of the ligand-HSA bonding was expected to give the ligand long blood retention. After 1 min of mixing with HSA, the ligand showed higher binding (1.7 times) than that of a control ligand (containing only activated disulfide). After intravenous injection to mice, the ligand half-lives were 1.6 and 9.2 times longer than those of control ligands with the active disulfide alone and with the alkyl chain alone, respectively. The proposed ligand has the potential to act as a platform for extending the half-life of small therapeutics in vivo.

In this study, hollow mesoporous silica nanoparticles (HMSN) coated with a 4T1 tumor cell membrane were used to construct biomimetic nanomaterials (DTX@CHMSN) for the treatment of breast cancer. The nanodrug can improve the water solubility of polyenetaxel (DTX) by taking advantage of the special structure, good biocompatibility, and adjustable surface chemical properties of HMSN. Hollow mesoporous silica nanoparticles are coated with 4T1 cell membranes derived from homologous tumors (CHMSN). Adhesion glycoproteins on cancer cell membranes specifically bind to receptors on the cell membranes of the same cancer cell to target specific breast cancer tissues. At the same time, the cell membrane of the 4T1 tumor also contains CD47 protein, which can be specifically recognized by the immune system to produce immune escape. Therefore, the biomimetic nanomedicine DTX@CHMSN, with homologous targeting and immune escape ability, can accumulate in large quantities at the tumor site, reduce systemic toxicity, and thus improve the therapeutic effect.

Selective targeting of cancer cells via overexpressed cell-surface receptors is a promising strategy to enhance chemotherapy efficacy and minimize off-target side effects. In this study, we designed peptide 31 (YHWYGYTPERVI) to target the overexpressed epidermal growth factor receptor (EGFR) in triple-negative breast cancer (TNBC) cells. Peptide 31 is internalized by TNBC cells through EGFR-mediated endocytosis and shares sequence and structural similarities with human EGF (hEGF), a natural EGFR ligand. Unlike hEGF, peptide 31 does not induce cell migration in TNBC cells. A novel conjugate of peptide 31 with doxorubicin (Dox) retains selectivity for TNBC cells and exhibits significant toxicity comparable to that of unconjugated Dox. Importantly, this conjugate shows no toxicity toward normal breast epithelial cells up to a high concentration (25 μM). Thus, peptide 31 serves as a versatile targeting ligand for developing novel conjugates with high selectivity for EGFR-positive cancers.

Dysregulation of translation is a hallmark of cancer that enables rapid changes in cellular protein production to shape oncogenic phenotypes. Translation initiation is governed by the m⁷GpppX cap-binding protein eukaryotic translation initiation factor 4E (eIF4E), the rate-limiting factor of cap-dependent translation initiation. eIF4E is overexpressed in many cancers and drives the production of oncoproteins that promote tumor growth and survival. Accordingly, eIF4E has been established as an attractive albeit challenging therapeutic target. Building upon our previous work of developing cell-permeable cap analogue prodrugs that inhibit eIF4E binding to the m⁷GpppX cap, herein we disclose the design of second-generation cap analogues with alternative N-9-substituted linkers which exhibit anticancer activity in BRAF^V600E mutant melanoma cell lines.

In recent years, targeted protein degradation (TPD) has emerged as a powerful therapeutic modality utilizing both heterobifunctional ligand-directed degraders (LDDs) and molecular glues (e.g., CELMoDs) to recruit E3 ligases for inducing polyubiquitination and subsequent proteasomal degradation of target proteins. The immunomodulatory drugs lenalidomide and pomalidomide bind to cereblon (CRBN), a substrate receptor of the CRL4A E3 ligase complex, to initiate degradation of neosubstrates critical for cell survival. Recently, nonlenalidomide or pomalidomide CRBN binders, known as alternate glutarimides, have gained popularity, offering potential degraders with varying physicochemical properties. Specifically, 3-substituted indazole derivatives have emerged as potent CRBN binders. We developed conditions for the direct cross-coupling of unprotected glutarimides with amines, streamlining the synthesis of alternative CRBN binders. This manuscript describes the rapid synthesis of 30 CRBN binders, their characterization as potential degraders and a cryo-EM structure of the CRBN/DDB1 with a representative compound (6).