MedChemComm最新文献

AXL is a promising antitumor target due to its important role in tumor growth, poor survival, metastasis, immunosuppression, and drug resistance. Herein, we employed molecular modeling-assisted structural optimization strategies to design and synthesize a series of penta- or hexa-bicyclo-pyrazolone derivatives as novel AXL inhibitors. Compounds with high enzymatic and cellular potencies against AXL are described. Compound w11 showed desirable selectivity for AXL kinase, preferable pharmacokinetic properties, and excellent antitumor efficiency in the MV-4-11 xenograft model. These favorable results demonstrated that compound w11 may serve as a promising therapeutic candidate for hematological malignancy.

Carbapenemases, β-lactamases hydrolysing carbapenem antibiotics, challenge the treatment of multi-drug resistant bacteria. The OXA-48 carbapenemase is widely disseminated in Enterobacterales, necessitating new treatments for producer strains. Diazabicyclooctane (DBO) inhibitors, including avibactam and nacubactam, act on a wide range of enzymes to overcome β-lactamase-mediated resistance. Here we describe investigations on how avibactam and nacubactam inhibit OXA-48 and two variants, OXA-163 and OXA-405, with deletions in the β5–β6 loop neighbouring the active site that modify activity towards different β-lactam classes. Nacubactam is ∼80-fold less potent than avibactam towards OXA-48, but this difference reduces in OXA-163 and OXA-405. Crystal structures and molecular dynamics simulations reveal electrostatic repulsion between Arg214 on the OXA-48 β5–β6 active-site loop and nacubactam, but not avibactam; effects absent from simulations of OXA-163 and OXA-405, which lack Arg214. Crystallographic and mass spectrometry data demonstrate that all three enzymes support desulfation of the bound DBOs. The results indicate that interactions with Arg214 affect DBO potency, suggesting that sequence variation in OXA-48-like β-lactamases affects reactivity towards inhibitors as well as β-lactam substrates.

Inhibition of the insulin-regulated aminopeptidase (IRAP) is a promising therapeutic strategy for neurodegenerative disorders such as Alzheimer's disease, due to its role in cognitive processes. HA08, a macrocyclic peptidomimetic derived from angiotensin IV, is among the most potent known IRAP inhibitors (IC₅₀ = 18 nM). However, detailed structure–activity relationship (SAR) studies at its C-terminus have been limited by synthetic constraints. Herein, we report the design, synthesis, and biological evaluation of a focused series of HA08 analogues to explore the impact of C-terminal modifications on IRAP inhibition. An improved divergent synthetic route was established via a common macrocyclic intermediate, enabling late-stage diversification through coupling with non-natural amino acids which led to the synthesis of twelve novel peptidomimetic scaffolds. Several analogues retained high potency, with one-carbon elongation next to the carboxylic acid moiety or secondary amine being well tolerated. In contrast, aliphatic analogues exhibited markedly reduced potency, highlighting the importance of π–π interactions, while the low activity of phenoxyacetic acid derivatives likely reflects altered geometry within the binding pocket. The most potent inhibitor in the series featured a C-terminal benzyl alcohol (IC₅₀ = 59 nM), approaching the activity of HA08. To rationalise these SAR trends, molecular dynamics simulations were performed based on the IRAP–HA08 co-crystal structure. Partial least squares analysis of protein–ligand contact patterns revealed that sustained interactions between the C-terminal carboxylate and Arg929 correlated with lower potency, whereas interaction with Arg439 was associated with enhanced activity. These findings suggest that subtle shifts in C-terminal positioning influence binding mode and potency and provides valuable insights for the design of future IRAP inhibitors.

Lysine-specific histone demethylase 1A (LSD1) is involved in epigenetic regulation and is a viable drug target with a number of LSD1 inhibitors in clinical trials. We report synthetic and structure–activity studies of two LSD1 inhibitors, TCP and SP2577, in clinical trials towards PROTAC development. 16 Heterobifunctional molecules were synthesised based on TCP and SP2577. No LSD1 degraders were identified in HCT116 cells, however two TCP analogues functionalised from the phenyl ring with an aklyl and PEG linker in combination with a VHL ligand demonstrated potent LSD1 inhibition in vitro in the HDAC1-CoREST-LSD1 complex (43 nM and 63 nM respectively). Our findings provide important SAR data towards LSD1 PROTACs.

The RET proto-oncogene is a critical oncogenic driver in the development of several types of cancer. Despite the existence of clinically approved RET inhibitors, their limited response rates and emergence of resistance due to diverse actionable mutations underscore the need for novel therapeutics. Herein, we report substituted imidazo[1,2-a]pyridine derivatives as new RET inhibitors exhibiting IC₅₀ values as low as 11 nM against three distinct point mutations and three important RET fusions. The binding mode and measured potency were elucidated by induced-fit docking simulations and cardiotoxicity was evaluated.

While cysteine targeting in kinases is well established and widely used, covalent interactions with other amino acids remain much less explored. We aimed to develop covalent inhibitors targeting tyrosine residues in the protein kinases JAK3 and MK2 using structure-based design principles to generate small sets of ligands containing tyrosine-reactive sulfonyl fluoride and the less-explored fluorosulfate warheads. While the JAK3 inhibitors failed to achieve covalent binding, the fluorosulfate-bearing MK2 inhibitor 42, which had been designed as an allosteric binder, unexpectedly formed a bond with the “catalytic” lysine, additionally uncovering a unique interaction at the hinge region. This highlights the untapped potential of fluorosulfates and provides a rare example of the use of this electrophile for lysine targeting in kinases. Our results highlight the limitations of traditional design methods and support the integration of fragment/lead-like covalent library screening to discover unanticipated interactions.

As therapeutic modalities increasingly diversify, the need for biophysical tools for routine characterisation of the underlying biomolecular targets and their noncovalent interactions is growing. In this Opinion article we discuss the role of native mass spectrometry (nMS), a mass spectrometry technique where the intact biomolecule and its noncovalent interactions are preserved during the analysis, to gain important insights to guide drug discovery and development. We conclude that nMS is one of the most powerful technologies available with potential to rapidly advance multiple stages of therapeutic discovery and development, yet it is arguably underutilised. Specifically, we highlight how nMS may progress research for contemporary therapeutic modalities including those implicated in targeted protein degradation, fragment-based drug discovery and mRNA therapies.

DNA-encoded libraries (DELs) are established as an effective screening strategy to identify protein ligands and offer a cost-effective means of screening large numbers of compounds. However, the synthesis and utilisation of DELs is implemented by relatively few laboratories. Here, we describe the design and synthesis of a medium-sized DEL through simple amide coupling procedures. We provide details of chemistry and enzymatic steps and demonstrate their effectiveness by synthesising 300 thousand and 3 million-member DELs. We demonstrate their integrity through screening against carbonic anhydrase IX and show their chemical diversity through in silico comparison with an established high-throughput screening library. The DELs described can be used as a resource to accelerate hit identification for early-phase drug discovery and are available to the academic community for screening.

MicroRNAs (miRNAs) regulate gene expression and the dysregulation in mature miRNA levels has been implicated in a wide variety of diseases. In particular, altered levels of mature microRNA-31 (miR-31) has been linked to a variety of different cancers. Targeting functionally relevant sites of the precursor structure of miR-31 with small molecules offer a strategy to regulate miR-31 maturation. Herein we describe a virtual screening approach to explore the druggability of the precursor structure of microRNA-31 (pre-miR-31). We used a structure-guided approach to virtually screen a fragment library and followed up with experimental characterization of top-ranking candidates, leading to the identification of several compounds that bound to pre-miR-31. Further characterization of the RNA-ligand complexes by heteronuclear single quantum coherence (HSQC) NMR spectroscopy revealed three compounds bound pre-miR-31 at the Dicer cleavage site, suggesting that these compounds may function to inhibit Dicer processing. Using these initial hits, we performed chemical structure similarity searches and identified additional binders of pre-miR-31 that had equivalent or enhanced binding relative to the parent compounds. These studies suggest a generalizable approach by which RNA-binding ligands can be identified from large chemical databases. These hits can then be further optimized to improve affinity and specificity for downstream functional assays.

CDK2 has emerged as a pivotal target in cancer chemotherapy. To develop a novel CDK2 inhibitor scaffold, multiple rational, structure-based design strategies were applied to known potent CDK2 inhibitors. Through retrosynthetic planning, chemical synthesis, and characterisation, compounds 2–8 were generated. Initial in vitro screening using the NCI-60 cancer cell line panel, followed by accurate cytotoxicity (GI₅₀) measurements, shortlisted compounds 5, 8b, and 8d as promising candidates. These compounds exhibited GI₅₀ values as low as 0.6 μM and demonstrated favourable safety profiles, with selectivity indices reaching up to 7.98. The top two active compounds, 5 and 8b, were further evaluated against the most sensitive cell line, MDA-MB-468 (breast cancer), at their respective GI₅₀ concentrations. Flow cytometric cell cycle analysis revealed 82% and 78% G1 phase arrest for compounds 5 and 8b, respectively, suggesting an effective CDK2/cyclin E targeting mechanism. Furthermore, annexin V-FITC apoptosis assays showed robust pro-apoptotic effects, with total apoptosis induction elevated 34.5-fold and 32.4-fold over the negative control for compounds 5 and 8b, respectively. Subsequent CDK2/cyclin E1 enzymatic inhibition assays confirmed the potency of these compounds, with IC₅₀ values of 3.92 nM for 5 and 0.77 nM for 8b, compared to 1.94 nM for the reference inhibitor roscovitine. Notably, the novel lead compound 8b exhibited approximately 2.5-fold greater potency than roscovitine. Molecular docking studies further supported the experimental findings and provided structural insights for future optimisation of this promising CDK2 inhibitor scaffold.