ACS Medicinal Chemistry Letters

Eleven-nineteen leukemia (ENL) is an epigenetic reader protein that drives oncogenic transcriptional programs in acute myeloid leukemia (AML). AML is one of the deadliest hematopoietic malignancies, with an overall 5-year survival rate of 27%. The epigenetic reader activity of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl marks on histone tails and colocalizes with promoters of actively transcribed genes that are essential for leukemia. Prior to the discovery of TDI-11055 , existing inhibitors of ENL YEATS showed in vitro potency, but had not shown efficacy in in vivo animal models...

Provided herein are novel PCSK9 inhibitors, pharmaceutical compositions, use of such compounds in treating cardiovascular diseases, and processes for preparing such compounds.

No abstract text is available yet for this article.

Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that affects many aspects essential to cell proliferation and survival. Recently, DHODH has been identified as a potential target for acute myeloid leukemia therapy. Herein, we describe the identification of potent DHODH inhibitors through a scaffold hopping approach emanating from a fragment screen followed by structure-based drug design to further improve the overall profile and reveal an unexpected novel binding mode. Additionally, these compounds had low P-gp efflux ratios, allowing for applications where exposure to the brain would be required...

The burgeoning interest in developing boron neutron capture therapy (BNCT) tracers and their accompanying diagnostics for the treatment of recalcitrant tumors has prompted this investigation. Our study aims to devise a tumor treatment strategy utilizing BNCT to target the αv β3 integrin. To this end, we propose a pioneering boron-infused cyclic Arg-Gly-Asp (RGD) peptide, cRGD(d-BPA)K, designed as an efficacious BNCT tracer. Additionally, we introduce its diagnostic complement, DOTA-cRGD(d-BPA)K, tailored for positron emission tomography (PET) to visualize αv β3 expressed tumors...

Herein, we report the design, the synthesis, and the study of novel triphenyl phosphonium-based nucleoside conjugates. 2'-Deoxycytidine was chosen as nucleosidic cargo, as it allows the introduction of fluorescein on the exocyclic amine of the nucleobase and grafting of the vector was envisaged through the formation of a biolabile ester bond with the hydroxyl function at the 5'-position. Compound 3 was identified as a potential nucleoside prodrug, showing ability to be internalized efficiently into cells and to be co-localized with mitochondria...

This Patent Highlight explores ground-breaking advancements in neurostimulation, psychedelic therapy, and brain function optimization from recent innovations. It examines methods for altering brain states through AI-driven non-invasive neurostimulation, potentially contributing to personalized brain therapy. The publication also delves into the therapeutic potential of N -isopropyl tryptamines and tryptamine derivatives. Furthermore, it discusses the therapeutic applications of psilocybin and psilocin crystalline forms in mental health and central nervous system disorders...

Provided herein are novel heterocyclic PAD4 inhibitors, pharmaceutical compositions, use of such compounds in treating multiple diseases, and processes for preparing such compounds.

Multidrug-resistant (MDR) strains of Staphylococcus epidermidis ( S. epidermidis ), prevalent in hospital environments, contribute to increased morbidity and mortality, especially among newborns, posing a critical concern for neonatal sepsis. In response to the pressing demand for novel antibacterial therapies, we present findings from synthetic chemistry and structure-activity relationship studies focused on arylsulfonamide/arylurea derivatives of aryloxy[1-(thien-2-yl)propyl]piperidines. Through bioisosteric replacement of the sulfonamide fragment with a urea moiety, compound 25 was identified, demonstrating potent bacteriostatic activity against clinical multidrug-resistant S...

Provided herein are novel pyrrolidinone derivatives as NIK inhibitors, pharmaceutical compositions, use of such compounds in treating inflammatory and autoimmune diseases, and processes for preparing such compounds.

This Patent Highlight explores ground-breaking advancements in pharmaceutical compositions, revealing the integration of serotonergic tryptamine compounds and microbial-produced biosurfactants. These innovations aim to enhance the bioavailability and efficacy of health-promoting substances significantly. The article examines the existing challenges in pharmacological treatments and the inventive solutions proposed by recent developments. It discusses compositions that reduce inflammation and improve mental and physical health, the use of serotonergic tryptamine compounds in mood and neurological disorders, and novel methods for boosting bioavailability with biosurfactants...

No abstract text is available yet for this article.

Forgotten natural products offer value as antimicrobial scaffolds, providing diverse mechanisms of action that complement existing antibiotic classes. This study focuses on the derivatization of the cytotoxin blasticidin S, seeking to leverage its unique ribosome inhibition mechanism. Despite its complex zwitterionic properties, a selective protection and amidation strategy enabled the creation of a library of blasticidin S derivatives including the natural product P10. The amides exhibited significantly increased activity against Gram-positive bacteria and enhanced specificity for pathogenic bacteria over human cells...

Next generation antimicrobial therapeutics are desperately needed as new pathogens with multiple resistance mechanisms continually emerge. Two oxaboroles, tavaborole and crisaborole, were recently approved as topical treatments for onychomycosis and atopic dermatitis, respectively, warranting further studies into this privileged structural class. Herein, we report the antimicrobial properties of 3-substituted-2( 5H )-oxaboroles, an unstudied family of medicinally relevant oxaboroles. Our results revealed minimum inhibitory concentrations as low as 6...

Selecting a known HTS hit with the pyrazolo[1,5- a ]pyrimidine core, our project was started from CMPPE, and its optimization was driven by a ligand-based pharmacophore model developed on the basis of published GABAB positive allosteric modulators (PAMs). Our primary goal was to improve the potency by finding new enthalpic interactions. Therefore, we included the lipophilic ligand efficiency (LLE or LipE) as an objective function in the optimization that led to a carboxylic acid derivative ( 34 ). This lead candidate offers the possibility to improve potency without drastically inflating the physicochemical properties...

Ferroptosis is a novel form of oxidative cell death triggered by iron-dependent lipid peroxidation. The induction of ferroptosis presents an attractive therapeutic strategy for human diseases, such as prostate cancer and breast cancer. Herein, we describe our design, synthesis, and biological evaluation of endogenous glutathione peroxidase 4 (GPX4) degraders using the proteolysis targeting chimera (PROTAC) approach with the aim of inducing ferroptosis in cancer cells. Our efforts led to the discovery of compound 5i (ZX703), which significantly degraded GPX4 through the ubiquitin-proteasome and the autophagy-lysosome pathways in a dose- and time-dependent manner...

No abstract text is available yet for this article.

Recent advancements in predictive medicine are significantly reshaping the field, primarily through developing novel NLRP3 inflammasome inhibitors and applying AI-driven predictive health analytics. NLRP3 inflammasome inhibitors offer new therapeutic strategies for treating inflammatory and neurodegenerative diseases. Concurrently, AI's role in predictive health analytics marks a transformative shift in disease management and personalized healthcare. By analyzing complex biomarker data, AI provides crucial insights into individual health trajectories, enabling early interventions and customized treatment plans...

Neuromedin U receptor 2 (NMUR2), which is expressed in the central nervous system (CNS) including the hypothalamus, has been noted as a therapeutic target against obesity. We previously reported that intranasal administration of CPN-219, a NMUR2-selective hexapeptide agonist, suppresses body weight gain in mice; however, there is no detailed information regarding its CNS effects. Recently, in addition to appetite suppression, stress responses and regulation of prolactin (PRL) secretion have also attracted attention...

The landscape of pharmaceutical R&D is being reshaped by the synergistic integration of Artificial Intelligence (AI) and groundbreaking drug discoveries, mainly focusing on MYC-modulating compounds and BET protein inhibitors. This Patent Highlight delves into this convergence, illustrating a transformative shift in the pharmaceutical industry's approach to drug development, strategic management, and treating various diseases, from cancer to inflammatory and fibrotic disorders.