ACS Medicinal Chemistry Letters最新文献

A type II Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) human kinase inhibitor GSK190937, with antiplasmodium activity against asexual blood stage parasites (PfNF54 IC₅₀ = 0.22 μM) was identified from the Kinase Chemogenomics Set, a collection of narrow-spectrum human kinase inhibitors. Medicinal chemistry progression of the hit focused on improving potency, selectivity, and ADME properties, leading to compounds 20, 23, and 29 with improved microsomal metabolic stability and asexual blood stage antiplasmodium activity. Mechanism of action studies showed that this series inhibits hemozoin formation, killing late-stage trophozoites.

Fyn proto-oncogene kinase (Fyn) and glycogen synthase kinase-3β (GSK-3β) belong to distinct branches of the protein kinase (PK) superfamily. Fyn is a member of the Src family of tyrosine kinases, whereas GSK-3β is classified within the CMGC group of serine/threonine kinases. Both play critical roles in neurodegenerative processes, and their dysregulation has been implicated in disease progression. The development of Fyn and GSK-3β inhibitors has attracted increasing research attention. The design of multitarget inhibitors represents a promising, though underexplored, therapeutic strategy. A recent study reported a series of dual selective nanomolar inhibitors based on structure–activity relationship (SAR) optimization. In-depth profiling of the lead compound’s neuroprotective and modulatory properties establishes a foundation for the development of next-generation neuroregenerative therapeutics.

We report findings on a novel family of nucleotide analogues with selective inhibitory activity against DNA polymerase theta (Polθ), a key enzyme in the theta-mediated end joining pathway and a critical player in synthetic lethality-based cancer therapies. Polθ’s intrinsically low fidelity, which contributes to genomic instability in homologous recombination-deficient tumors, was probed for selective targeting by these analogues. The newly identified compounds feature an all-carbon stereogenic quaternary center at either the C3′ or C2′ position of the furanoside ring, a structural modification that has already demonstrated potential in antiviral, anticancer, and cardioprotective applications. Biochemical assays suggest these analogues exploit Polθ’s unique active site architecture, offering a possible direction for overcoming PARP inhibitor resistance and enhancing personalized cancer treatment strategies.

Efflux pump-mediated multidrug resistance is a common mechanism by which cancer cells reduce the efficacy of a broad range of small-molecule therapeutics. We discovered that substituting the 4′-hydroxy group of doxorubicin─a known efflux pump substrate─with an epi-amino group results in a new compound, doxorubamine, which exhibits substantially improved activity against drug-sensitive and -resistant cancer cells and organoids. Mechanistic studies reveal that doxorubamine is a poor substrate of P-glycoprotein, and it thus retains high potency against multidrug-resistant cancer. This synthetic modification provides a promising strategy for circumventing multidrug resistance beyond conventional approaches that rely on efflux pump inhibition.

Motivated by promising clinical trial data for the combination of the histone deacetylase 6 (HDAC6) inhibitor ricolinostat with the proteasome inhibitor bortezomib in relapsed/refractory multiple myeloma (MM) patients, we engineered dual HDAC6/proteasome inhibitors. FDA-approved HDAC inhibitors suffer from off-target effects, which have been attributed, in part, to their lack of HDAC isoform selectivity. Furthermore, they are potentially mutagenic, because of their indispensable hydroxamic acid zinc-binding groups (ZBGs). Deploying the HDAC6-selective phenyl-4-hydroxamic acid motif, and O-carbamoylated hydroxamates as hydroxamic acid surrogates, then grafting to the electrophilic boronic acid warhead of bortezomib/ixazomib, we discovered several dual HDAC6/proteasome inhibitors that were potent in cell-free assays, inhibiting the chymotrypsin-like (CL) proteasomal activity on par with that of bortezomib, and many compounds demonstrated selectivity for HDAC6 over HDAC1 as predicted. Moreover, several dual HDAC6/proteasome inhibitors were submicromolar inhibitors of MM cell growth. Of particular interest, AMC-3-030 with an O-(N-phenylcarbamoyl)hydroxamate ZBG emerged as an exciting lead for further studies.

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.