ACS Medicinal Chemistry Letters最新文献

Membrane-associated carbonic anhydrase (CA IX) is overexpressed in multiple cancers, making it a compelling target for therapeutics, yet measuring small molecule binding is challenging outside its native environment. Surface Plasmon Resonance Microscopy (SPRM) enables label-free kinetic measurements on whole cells, revealing critical insights that are often missed by conventional assays that require receptor purification. Here, we pioneer the use of SPRM to study kinetic interactions of five sulfonamide-based small molecule inhibitors (Acetazolamide, Sulfanilamide Furosemide, Dansylamide, and 4-Carboxybenzenesulfonamide(4-CBS)) with CA IX on live Ramos B suspension cells. SPRM measurements were in close agreement with the literature and demonstrated a low coefficient of variation (% CV) of 6.8%. Additionally, Sulfanilamide demonstrated a 16-fold stronger affinity in its native membrane-bound state than in its purified state. This pioneering study establishes SPRM for label-free kinetic measurements of small molecule interactions on live suspension cells in vitro.

Provided herein are novel compounds, pharmaceutical compositions, use of such compounds in treating hemoglobinopathies, namely, anemia, sickle cell disease, or thalassemia, and processes for preparing such compounds.

Provided herein are novel compounds as glucagon receptor agonists, pharmaceutical compositions, use of such compounds in treating type 2 diabetes mellitus and obesity, and processes for preparing such compounds.

Recent advances in targeted protein degradation combine dual E3 ligase–recruiting multivalent PROTACs, Survivin as a predictive biomarker for therapeutic responsiveness, and dendrimer–PROTAC conjugates for CNS and inflammation-targeted delivery. Together, these innovations form a synergistic framework for potent, selective, and biomarker-guided degraders with enhanced delivery, offering a promising blueprint for next-generation therapeutics in oncology and beyond.

Hydrogenation reactions are commonly employed to reduce organic functional groups, but traditional approaches often rely on hazardous compressed gases and pyrophoric catalysts. Motivated by the need for safer and more practical alternatives, we developed a broadly applicable protocol for Cbz group removal that avoids both flammable Pd/C and hydrogen cylinders. Instead, we utilize SiliaCatPd(0)─a commercially available, sol–gel supported palladium─which has demonstrated effectiveness in debenzylation processes. The unique sol–gel matrix of this catalyst minimizes metal leaching and mitigates the risks associated with pyrophoric palladium sources. Leveraging these advantages, our method offers a safer and more convenient route for hydrogenation in everyday laboratory practice. Specifically, we present a transfer hydrogenation system using this supported palladium catalyst for the selective deprotection of Cbz-protected amines, designed to streamline medicinal chemistry workflows with rapid setup and execution in a microwave reactor.

DNPH1 is a hydrolase enzyme that degrades the noncanonical nucleotide 5-hydroxymethyl-2′-deoxyuridine 5′-monophosphate (hmdUMP), thus acting as a nucleotide pool sanitizer by preventing its aberrant incorporation into DNA. Recent studies have shown that loss of DNPH1 enhances the sensitivity of homologous recombination repair-deficient cancer cells to PARP inhibitors, highlighting its potential as an attractive therapeutic target. Herein we report the design and prosecution of an integrated hit finding strategy combining high-throughput screening, DNA-encoded library screening, and fragment-based lead generation which enabled the discovery of the first non-nucleotide ligands for DNPH1. We compare four hit compounds which differ markedly in their chemical structures, physicochemical properties, and binding modes and summarize parallel hit-to-lead workup efforts. We also provide discussion of the merits of an integrated approach for hit discovery when applied to challenging novel targets such as DNPH1.

Recent advances showcase catalytic and selective strategies that move beyond conventional inhibition or immunosuppression. These include degraders targeting resistant EGFR, antibodies depleting CD7+ pathogenic lymphocytes, ADAR-based RNA sensors for drug discovery, and quinazoline inhibitors penetrating the brain to block C797X double mutants. Together, these platforms illustrate convergent approaches to dismantle disease drivers at protein, immune, RNA, and signaling levels.

Recent innovations showcase the power of selectivity in precision medicine. Brain-penetrant TYK2 inhibitors target autoimmune and neuroinflammatory disease, fetal cell diagnostics improve prenatal screening, and biomarker signatures refine checkpoint immunotherapy. Together, these advances highlight how molecular, cellular, and patient-level selectivity drives therapeutic precision across neurology, oncology, immunology, and reproductive health, reshaping diagnostics and treatment strategies from early development through complex disease.

Targeted protein degradation, next-generation antibody discovery, and spatial multiomics are reshaping therapeutic strategies across oncology, immunology, and neurology. Recent innovations include platelet-sparing degraders of BCL-XL for cancer treatment, rare antibody recovery platforms for challenging antigens, in situ sequencing for immune repertoire mapping, and senolytic PROTACs that target pain-associated neurons. Together, these approaches exemplify how mechanistic precision and synergistic platforms can accelerate therapeutic breakthroughs.