ACS Medicinal Chemistry Letters最新文献

This patent application illustrates a series of cyclic peptides inhibiting Interleukin-23 (IL-23), as represented by Formula I. These cyclic peptides exhibit significant therapeutic potential for treating diseases and disorders associated with IL-23 imbalance, with a particular focus on inflammatory bowel disease (IBD).

TMTP1 is a tumor-homing peptide that selectively targets highly metastatic tumor cells with XPNPEP2 identified as its potential targeting receptor. Although TMTP1-based molecular probes have been explored for imaging tumors such as hepatocellular carcinoma (HCC), their clinical translation has been hampered by factors including suboptimal tumor uptake and rapid systemic clearance. To study possible solution for addressing these challenges, a cyclic TMTP1 based positron emission tomography (PET) probe, [⁶⁸Ga]Ga-DOTA-cTMTP1, was designed, synthesized, and evaluated for imaging HCC in small animal models. [⁶⁸Ga]Ga-DOTA-cTMTP1 demonstrated favorable aqueous solubility, with a log D_7.4 value of −3.28 ± 0.05, and it exhibited excellent in vitro stability in phosphate buffered saline (PBS) and fetal bovine serum (FBS). Biodistribution studies revealed a certain level of tumor accumulation (0.98 ± 0.14%ID/g at 30 min) and retention (0.40 ± 0.11%ID/g at 120 min). Impressively, [⁶⁸Ga]Ga-DOTA-cTMTP1 maintained high tumor-to-liver contrast over time, with ratios of 2.65 ± 0.45 at 30 min, 2.37 ± 0.07 at 60 min, and 2.14 ± 0.20 at 120 min. It also displayed capability of clear visualization of small HCC foci (<4 mm) in transgenic c-Myc liver tumor mice models, with tumor/liver ratios 2.20 ± 0.10 at 30 min, 2.26 ± 0.11 at 60 min, and 2.55 ± 0.44 at 120 min, respectively. Overall, this study highlights that [⁶⁸Ga]Ga-DOTA-cTMTP1 has favorable pharmacokinetic and in vivo tumor imaging profile, and it is a highly promising probe for visualization of HCC microlesions. Development of PET probes based on cyclic TMTP1 is a promising approach for discovering novel imaging probes.

This highlight presents novel 6-aryl isoindolin-1-one derivatives that developed as negative allosteric modulators (NAMs) of metabotropic glutamate receptor 2 (mGluR₂). Chemical synthesis and potency (IC₅₀) data for both mGluR₂ and mGluR₃ are disclosed.

Fibroblast activation protein (FAP) is an attractive biomarker for tumor-targeting agents in cancer diagnosis and therapy. FAP-2286 shows retention in FAP-expressing tumors and is known as a promising FAP-targeting radioligand. In this study, we aimed to develop a FAP-2286 derivative that demonstrates higher tumor retention than FAP-2286. We designed DOTAGA-FAP-2286 and DOTAGA-FAP-2286-ALB by replacing DO3A with 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAGA) and introducing an albumin binder. Both compounds were successfully radiolabeled with ¹¹¹In. Compared with [¹¹¹In]In-DOTAGA-FAP-2286, [¹¹¹In]In-DOTAGA-FAP-2286-ALB showed higher stability in murine plasma. In the cell competition binding study, In-DOTAGA-FAP-2286-ALB exhibited a higher FAP-binding affinity than In-DOTAGA-FAP-2286. In the albumin-binding assay, [¹¹¹In]In-DOTAGA-FAP-2286-ALB showed a high binding rate in the solution with albumin. The biodistribution assay revealed marked tumor retention of [¹¹¹In]In-DOTAGA-FAP-2286-ALB, resulting in the enhancement of predicted tumor AUC values of [²²⁵Ac]Ac-DOTAGA-FAP-2286-ALB. These results suggest advantages of the introduction of an albumin binder to FAP-2286.

The relatively polar 4(1H)-pyridone (4-pyridone) heterocycle is found in many drugs and drug candidates. In a comparison of the hydrophobicity, aqueous solubility, and metabolic stability of several matched sets of 4-pyridones, 4(1H)-quinolones (4-quinolones), and 9(10H)-acridones (9-acridones), measured chromatographic log D_7.4 values show that 9-acridones are more hydrophobic and less soluble than their 4-quinolone and 4-pyridone counterparts. All 4-pyridone/4-quinolone pairs had identical or very similar hydrophobicity and aqueous solubility properties. Metabolic stability increased steadily from 9-acridones to 4-quinolones to 4-pyridones, consistent with the progressive increase in Fsp³ values and log D. The gain in metabolic stability was not as great for those 4-pyridone/4-quinolone pairs featuring additional polar functional groups/heterocycles.

Small molecules that covalently modify proteins typically contain an electrophile that selectively reacts with nucleophilic residues in a protein target, such as cysteine, serine, and threonine. Targeting other amino acids is an emerging strategy in covalent probe design. This study reports the discovery and characterization of the covalent reaction between a novel allene warhead and a histidine residue in the active site of the bacterial thiol–disulfide oxidoreductase enzyme Escherichia coli DsbA (EcDsbA). Allenes have not been widely reported for their use as covalent warheads. The interaction was characterized by X-ray crystallography, nuclear magnetic resonance spectroscopy, and mass spectrometry. This analysis provided insights into the structure, reaction rate, and selectivity of the allene. Investigation of the reactivity with nucleophilic amino acids revealed that the reaction with the allene warhead shows some specificity for the histidine in the active site of EcDsbA. Thus, the allene represents a novel histidine-modifying warhead.

A small library of novel thiazolidinone-based sulfonamide derivatives was designed, synthesized and evaluated for their ability to target human carbonic anhydrase (hCA) isoforms IX and XII, which are overexpressed in malignant cells and play a key role in metastasis and therapeutic response of cancer cells. A molecular hybridization approach was employed to design the molecules by combining different moieties identified as having antitumor activity. The thiazolidinone core was functionalized with benzenesulfonamide as a zinc-binding group and different isatin derivatives to enhance the chemical profile and optimize the hydrophilic/lipophilic balance. Biological evaluation against hCA I, II, IX and XII isoforms showed promising inhibitory activities, and some compounds exhibited selectivity and high inhibitory activity against hCA IX and hCA XII while not affecting off-target hCA I and hCA II. In particular, compound 3h demonstrated high selectivity with K_i values of 57.8 nM for hCA IX and 44.3 nM for hCA XII.

Nitric oxide synthase (NOS) is a pivotal enzyme that regulates various physiological processes, and the dysregulation of neuronal NOS (nNOS) is implicated in neurodegenerative diseases. In our efforts to leverage existing X-ray crystallography data to develop novel aminoquinoline–pyridine hybrid inhibitors and evaluate their inhibitory activities and interactions with NOS isoforms, we identified compounds 8 and 9 as potent human nNOS inhibitors (K_i = 38 and 22 nM, respectively). Notably, compound 8 displayed an unprecedented binding mode, displacing the essential cofactor tetrahydrobiopterin (H₄B). Furthermore, compound 9 exhibited excellent selectivity, with a 900-fold preference for human nNOS over human eNOS, making it one of the most potent and selective aminoquinoline-based nNOS inhibitors reported to date. Herein we present our inhibitor design rationale, the synthesis, and the biochemical/physical evaluation of binding along with X-ray crystallographic studies with three NOS isoforms, providing detailed insights into the observed potency and selectivity of these inhibitors.

The bromodomain and extra-terminal domain (BET) protein family is a class of epigenetic reader proteins that recognize N-acetylated lysine residues in histone tails, playing a crucial role in gene expression and cell transcription. Selective inhibition of bromodomain-containing proteins (BRDs) disrupts transcription in key oncogenes. Over the past decade there has been considerable interest in developing small molecule BET inhibitors for the treatment of hematological malignancies and solid tumors. Herein, we report the development of a triazinoindole scaffold capable of the inhibition of bromodomain-containing protein 4 (BRD4), with either dimethylisoxazole or dimethyltriazole substituents acting as chemomimetics of the N-acetylated lysine residues. Derivatization of the parent scaffold afforded the lead compound, which displays low nanomolar affinity toward BRD4-BD1 with a favorable physicochemical and in vitro stability profile.