ACS Medicinal Chemistry Letters最新文献

Lenacapavir (LEN) is a new, first-in-class, long acting, HIV-1 capsid (CA)-targeting inhibitor for treating multidrug-resistant HIV-1 infections. LEN exhibits high potency against all major HIV-1 subtypes including variants resistant to current antiretroviral therapies providing a life-saving opportunity for heavily treatment-experienced adults with multidrug-resistant HIV-1. Despite this, LEN has a relatively low barrier to viral resistance. Clinical trials identified resistance-associated mutations near LEN binding site, with the M66I variant exhibiting highest level of resistance (>3200-fold). These findings necessitate continuing efforts to develop next-generation inhibitors against emerging LEN-resistant mutation. We focused on identifying LEN structural functionalities amenable to modifications and to develop LEN analogs with improved antiviral activity against the M66I mutant. Here, we report a new LEN analog, KFA-027, with substantially improved antiviral activity (EC₅₀ ∼ 444 nM, >20-fold) against M66I variant. Overall, these findings suggest a route for developing next-generation LEN analogs against WT and emerging drug-resistant CA mutations.

Cdc2-like kinase (CLK) inhibitors represent an innovative class of small molecules designed to modulate RNA splicing patterns, offering a novel avenue for therapeutic intervention in diseases where dysregulated splicing contributes to pathogenesis, particularly in oncology. Here, we describe the discovery of Rogocekib (CTX-712), a promising therapeutic candidate as a CLK inhibitor, which is currently in clinical development. Our medicinal chemistry research involved structure-based drug design-guided scaffold hopping from an initial chemical scaffold and subsequent chemical optimization to generate a novel 1H-imidazo[4,5-b]pyridine series. Treatment with CTX-712 reduced the phosphorylation of serine- and arginine-rich proteins in a dose-dependent manner, leading to potent in vitro cell growth suppression and in vivo antitumor activity in lung cancer NCI-H1048 xenograft model. These findings highlight the promise of CTX-712 as a novel CLK inhibitor and its potential as a therapeutic for cancers, particularly those characterized by RNA splicing alterations.

The ubiquitin-independent proteasome system has emerged as an attractive point of intervention for a variety of diseases, including neurodegenerative diseases. Though inhibition of this system has been studied for decades, 20S proteasome enhancement is much younger by comparison, but substantial levels of progress have been made in this field especially within the last five years. This microperspective will highlight these advancements, focusing on the novel developments being made in designing potent enhancers and evaluating them in disease-relevant systems.

A novel series of triazole-tethered monoterpenoid–lignan hybrid molecules has been designed to target xanthine oxidase (XO), the enzyme responsible for hyperuricemia when it is up-regulated, resulting in gout and other metabolic disorders. Designed molecules were synthesized and initially evaluated for their XO inhibitory potential, and MT7 was most active (XO: IC₅₀ = 0.263 ± 0.06 μM) with radical scavenging efficacy. MT7 showed higher cytotoxic potential against XO harboring cancer cells (MBDA-MB-231 breast cancer cells) than non-XO-harboring cells (A547 skin cancer cells), confirming intracellular XO inhibition. MT7 was nontoxic to mouse fibroblast cells (L929) and had favorable pharmacokinetic profiles. In vivo investigations in rodent-based animal models revealed the LD₅₀ (300 mg/kg) value of MT7 and a dose-dependent reduction in serum uric acid. Overall, this suggests MT7 as an effective lead molecule for further investigations as a potential clinical candidate for the management of hyperuricemia via XO inhibition.

Aurora kinase A, a serine-threonine kinase frequently overexpressed in cancers, remains unaddressed by clinically approved inhibitors. Our previously endeavors unveiled a unique class of quinazolin-4-amine derivatives as potent, selective Aurora A kinase inhibitors. To further enhance therapeutic potential and Aurora A selectivity, we conducted systematic structural optimization and developed compound 5h, which exhibits potent antiproliferative activity across human cancer cell lines─particularly in triple-negative breast cancer MDA-MB-231 cells. Crucially, 5h exhibits 362-fold selectivity for Aurora A over Aurora B, a critical feature for therapeutic efficacy and safety. Molecular dynamics simulations reveal its selectivity arises from unique C–H/π interactions, enhanced hydrophobic contacts, an open Aurora A binding pocket, and tighter protein packing. At submicromolar concentrations, 5h effectively suppresses Aurora A autophosphorylation. Furthermore, it significantly inhibits tumor growth in MDA-MB-231 xenograft models, supporting its development as a promising anticancer candidate.

Peptide-based inhibitors exhibit considerable potential as antiviral agents targeting SARS-CoV-2. In this study, we designed analogs (TLP-1, TLP-2, and TLP-3) of Temporin L (TL) peptide with the specific objective of selectively interacting with and targeting the main protease (Mpro) of SARS-CoV-2. The synthesis and characterization of TLPs were employed using solid-phase peptide synthesis and LC-MS respectively. CD and solution NMR spectroscopy elucidated the overall structure of the TLPs relative to TL, revealing folded peptides where introduced mutations alter the peptide conformation for binding to Mpro. MD simulations highlighted improvements in TLP’s stability and interactions with Mpro. FRET based protease activity assays provided evidence that TLPs exhibited enhanced inhibitory activity against Mpro. The results of our study reveal the promising prospects of TLPs as attractive candidates for in vivo investigations, thereby contributing to the progress of peptide-based therapeutic approaches targeting SARS-CoV-2.

Polybromo-1 (PBRM1) is a key subunit of the PBAF chromatin remodeling complex, linking histone lysine acetylation to transcriptional regulation through six tandem bromodomains. Targeting PBRM1 bromodomains offers therapeutic potential in prostate cancer and clear cell renal cell carcinoma. Most existing PBRM1 inhibitors also bind the structurally related SMARCA2/4 bromodomains and lack target selectivity. We and others recently developed selective PBRM1 bromodomain inhibitors that do not bind the SMARCA2/4 bromodomains. However, the key residues and binding interactions leading to selectivity for PBRM1 were unknown. Here, we solved an X-ray crystal structure of PBRM1-BD2 bound to our selective PBRM1 bromodomain inhibitor (PB16). Through mutagenesis, we identify a unique tyrosine residue in PBRM1 that creates a distinct binding pocket essential for selective inhibitor binding. Unlike GNE-235, another selective PBRM1 bromodomain inhibitor, PB16 demonstrates cell activity in PBRM1-dependent cancer models, making it a promising lead candidate to further develop for targeted cancer therapy.

Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) has emerged as a powerful strategy for disease treatment. By recruiting E3 ligases, these molecules enable selective degradation of pathogenic proteins. Cereblon (CRBN), a key component of the CUL4-DDB1-CRBN E3 ligase complex, is the most commonly recruited E3 ligase in PROTACs, including those targeting histone deacetylases (HDACs). In this study, we designed SZ-2, a bifunctional molecule derived from the DDB1 ligand MM-02-57 and the HDAC inhibitor vorinostat, to simultaneously bind DDB1 and HDACs. SZ-2 effectively induced degradation of HDAC1 and HDAC2 and demonstrated potent anti-multiple myeloma activity, highlighting its potential as a novel therapeutic agent.

The SWI/SNF chromatin remodeling complex regulates numerous cellular processes, and inactivating mutations in its subunit, SMARCA4, are closely associated with various malignancies. The inactivation of SMARCA4 has been found to have a synthetic lethal relationship with the inhibition of SMARCA2 ATPase, suggesting that targeted inhibition of SMARCA2 ATPase in SMARCA4-deficient environments presents a promising tumor treatment option. In this study, we identified binding pockets with selective modification potential through mixed-solvent molecular dynamics simulations. Additionally, several selective inhibitors of SMARCA2 ATPase were identified by virtual screening, and preliminary structural modifications were conducted. Among them, compounds 4 and 11 demonstrated inhibitory activity at micromolar level and exhibited selectivity. Overall, these findings validate the efficacy of our virtual screening approach and provide a promising novel scaffold for the development of highly selective SMARCA2 ATPase inhibitors.