ACS Medicinal Chemistry Letters最新文献

We were attracted to the therapeutic potential of inhibiting Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING E3 ligase that plays a critical role in regulating the activation of T cells. However, given that only protein–protein interactions were involved, it was unclear whether inhibition by a small molecule would be a viable approach. After screening an ∼6 billion member DNA-encoded library (DEL) using activated Cbl-b, we identified compound 1 as a hit for which the cis-isomer (2) was confirmed by biochemical and surface plasmon resonance (SPR) assays. Our hit optimization effort was greatly accelerated when we obtained a cocrystal structure of 2 with Cbl-b, which demonstrated induced binding at the substrate binding site, namely, the Src homology-2 (SH2) domain. This was quite noteworthy given that there are few reports of small molecule inhibitors that bind to SH2 domains and block protein–protein interactions. Structure- and property-guided optimization led to compound 27, which demonstrated measurable cell activity, albeit only at high concentrations.

Two series of ten new 1,2,4-trisubstituted imidazolin-5-ones were synthesized and screened against MCF-7 breast cancer and A549 lung cancer cell lines to test their potential in vitro anticancer activity. The results revealed preferential activity of the tested compounds toward MCF-7 cell lines compared to A549 cell lines. The most promising ten compounds (3a, 3c, 3f, 3g, 3h, 3i, 3j, 6a, 6f, and 6i) were subjected to VEGFR-2 enzyme inhibitory activity testing to further explore their mechanism of action. The tested compounds showed remarkable enzyme inhibition in micromolar concentrations ranging from 0.07 to 0.36 μM, compared with Sorafenib and Sunitinib with IC₅₀ values of 0.06 and 0.12 μM, respectively. The most promising candidate, 3j, was further evaluated for its cell cycle phases, apoptotic induction ability, as well as its antiproliferative activity and inhibitory potential for endothelial cell migration, analyzed by a cell scratch assay. Furthermore, in silico studies were also performed to identify and detect the stability of the binding poses.

Blocking the immunosuppressive function of T-cell immunoglobulin mucin-3 (TIM-3) is an established therapeutic strategy to maximize the efficacy of immune checkpoint inhibitors for cancer immunotherapy. Currently, effective inhibition of TIM-3 interactions relies on monoclonal antibodies (mAbs), which come with drawbacks such as immunogenicity risk, limited tumor penetration, and high manufacturing costs. Guided by the X-ray cocrystal structures of TIM-3 with mAbs, we report an in silico structure-based rational design of constrained peptides as potent TIM-3 inhibitors. The top cyclic peptide from our study (P2) binds TIM-3 with a K_D value of 166.3 ± 12.1 nM as determined by surface plasmon resonance (SPR) screening. Remarkably, P2 efficiently inhibits key TIM-3 interactions with natural TIM-3 ligands at submicromolar concentrations in a panel of cell-free and cell-based assays. The capacity of P2 to reverse immunosuppression in T-cell/cancer cell cocultures, coupled with favorable in vitro pharmacokinetic properties, highlights the potential of P2 for further evaluation in preclinical models of immuno-oncology.

2-Arachidonoyl glycerol (2-AG) is the principal endogenously produced ligand for the cannabinoid CB1 and CB2 receptors (CBRs). The lack of potent and efficacious 2-AG ligands with resistance against metabolizing enzymes represents a significant void in the armamentarium of research tools available for studying eCB system molecular constituents and their function. Herein we report the first endocannabinoid glyceride templates with remarkably high potency and efficacy at CBRs. Two of our lead chiral 2-AG analogs, namely, (13S)- and (13R)-Me-2-AGs, potently inhibit excitatory neurotransmission via CB1 while they are endowed with excellent resistance to the oxidizing enzyme COX-2. Our SAR results are supported by docking studies of the key analog and 2-AG on the crystal structures of CB1.

Herein we describe the discovery of a 2-aminopyridine scaffold as a potent and isoform selective inhibitor of the Na_v1.8 sodium channel. Parallel library synthesis, guided by in silico predictions, rapidly transformed initial hits into a novel 2-aminopyridine lead class possessing good ADME and pharmacokinetic profiles that were able to display activity in a clinically translatable nonhuman primate capsaicin-sensitized thermode pharmacodynamic assay. Progress toward the lead identification, optimization, and in vivo efficacy of these compounds will be discussed.

Neuromedin U (NMU) activates two types of receptors (NMUR1 and NMUR2), and the former is mainly expressed in the peripheral tissues, including the intestinal tract and lung tissues. Since NMUR1 contributes to the promotion of type 2 inflammation in these tissues, it is a potential target to suppress inflammatory responses. However, promising antagonist candidates for human NMUR1 have not yet been developed. Here we successfully identified pentapeptide antagonist 9a through a structure–activity relationship study based on hexapeptide lead 1. Its antagonistic activity against human NMUR1 was 10 times greater than that against NMUR2. This is a breakthrough in the development of NMUR1-selective antagonists. Although 9a was relatively stable in the plasma, the C-terminal amide was rapidly degraded to the carboxylic acid by the serum endopeptidase thrombin, which acted as an amidase. This basic information would aid in sample handling in future biological evaluations.

In this study, a focused library of oxime ester derivatives of 2,4-dichloro-5-sulfamoylbenzoic acid (lasamide) containing Schiff bases was synthesized and tested in vitro for their ability to inhibit the cytosolic human carbonic anhydrases (hCAs) I and II, as well as the transmembrane and tumor-associated IX and XII isoforms. As a result, we obtained a first line of knowledge on lasamide derivatives potentially useful for development as CA inhibitors (CAIs). In particular, we focused our attention on the derivative 11, which was selective toward hCAs IX and XII over the cytosolic isoenzymes. An in silico study was conducted to assess the binding mode of 11 within hCAs IX and XII. Also, antiproliferative assays highlighted promising derivatives. The data obtained in this study are currently in use for the development of better-performing compounds on the tumor-associated isoforms.

Provided herein are novel KRAS inhibitors, pharmaceutical compositions, use of such compounds in treating non-small-cell lung cancer, and processes for preparing such compounds.

Herein, we report the modular synthesis and immunological activity of seven bis-aryl triazole trehalolipids (1a–1g) as Brartemicin analogs. The compounds comprised one or two octyloxy (C8) alkyl chains and were synthesized using the venerable CuAAc reaction between the respective aryl acetylenes and a trehalose diazide. A Mincle reporter cell assay revealed that all lipidated analogs activated Mincle. Two compounds, 1c and 1d, produced strong Mincle-dependent immune responses in vitro. The activity was dependent on the degree of alkylation and regiochemistry, with 1c and 1d showing significantly increased IL-1β production in vitro compared to monoalkylated compounds and dialkylated compounds lacking ortho substitution. Molecular docking of 1c positioned the triazole in proximity to Arg-183, which may offer additional interactions that could explain the binding affinity for this class of ligand. These findings demonstrate the capability of triazole-linked Brartemicin analogs as Mincle-mediated Th1/Th17 vaccine adjuvants.