ACS Medicinal Chemistry Letters最新文献

Drug patents are an important aspect of academic and industrial collaboration in drug discovery, including innovation of new drug candidates, the procedure of receiving granted patents of new drugs, and protecting them in the market and courts. The Microperspective considers various modes of collaboration between academics and industry: classic and nonclassic modes of academic patent licensing to the industry, academics used in patent litigations as expert witnesses, assessors, and amicus briefs.

Provided herein are novel imidazopyridazine compounds as IL-17 inhibitors, pharmaceutical compositions, use of such compounds in treating inflammatory diseases, and processes for preparing such compounds.

Provided herein are novel compounds as TREM2 agonists, pharmaceutical compositions, use of such compounds in treating Alzheimer’s disease, and processes for preparing such compounds.

Oxidative damage and cholinergic dysfunction are common pathological features of Alzheimer’s disease (AD). Maintaining the redox balance of neurons and cholinergic signaling through antioxidants and acetylcholinesterase (AChE) inhibition may provide therapeutic benefits for AD. In this regard, we discovered three AChE inhibitors with more potency than the positive control (rivastigmine; IC₅₀ = 24.5 μM). Among these active compounds, C5 (a flavonoid derivative) was the most potent AChE inhibitor with an IC₅₀ of 5.02 μM, followed by C1, C6, and C2 with IC₅₀ values of 7.94 μM, 8.13 μM, and 27.52 μM, respectively. Compound C5 also demonstrated strong neuroprotective activity, rescuing PC12 cells from H₂O₂-induced damage and scavenging various ROS models. Interestingly, C5 also prevented memory impairments in the scopolamine-induced cognitive dysfunction zebrafish model. Our findings suggest that C5 is a potential drug lead for cholinergic dysfunction-related disorders such as AD.

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.