Journal of Medicinal Chemistry最新文献

A library of potent WEE1 kinase inhibitors was synthesized based on the discontinued frontrunner clinical candidate AZD1775 (1), many of which were more selective for WEE1 over an undesirable off-target of 1, the kinase PLK1. When tested against patient-derived organoids (PDOs) grown from TP53-mutated colorectal cancer (CRC) peritoneal metastases, 34 (IC₅₀ value of 62 nM) exhibited stronger efficacy than 1 (IC₅₀ value of 120 nM) and the best-in-class clinical candidate ZN-c3 (IC₅₀ value of 127 nM). Against primary CRC PDOs with TP53-WT, 34 significantly enhanced DNA damage, replication stress and apoptosis compared to 1, as well as demonstrated high selectivity over patient-matched normal healthy colon PDOs, highlighting a potential therapeutic window for cancer treatment. Overall, this investigation provides critical insight into several potent WEE1 inhibitors that exhibited exceptional efficacy against CRC PDOs and is the first to utilize a PDO platform to assess their effect on healthy and malignant cell viability.

The α7 nicotinic acetylcholine receptors (nAChRs), identified in peripheral and central nervous systems, are crucial for cognitive function, memory, inflammation, and are linked to disorders like Alzheimer’s disease (AD), lung cancer, myasthenia gravis, and atherosclerosis. Here we report that a novel α4/7-conotoxin (CTx) LvID, from Conus lividus, potently inhibits rat α7 nAChRs expressed in Xenopus oocytes with an IC₅₀ of 13.8 nM, showing little activity against other rat nAChR subtypes. The structure of LvID was elucidated using nuclear magnetic resonance (NMR) spectroscopy and comprises a short helix braced by disulfide bonds. The key residues of LvID that bind to the α7 nAChRs were determined from a series of alanine mutants. Molecular simulation provided a possible explanation for the activity and specificity of LvID binding to α7 nAChRs. This finding offers a vital pharmacological tool for investigating the structural features and functional mechanisms of α7 nAChRs.

Proteolysis Targeting Chimeras (PROTACs) represent promising therapeutic modalities for degrading disease-causing proteins. However, the development of effective PROTACs has been limited by the availability of suitable E3 ligase ligands. In this study, we demonstrate for the first time that SPOP, an unexplored E3 ligase, can be recruited to degrade target proteins of interest. We developed a bridged PROTAC strategy and successfully discovered a proof-of-concept PROTAC degrader 9 (MS479), which recruits the E3 ligase SPOP by directly binding its substrate GLP as a bridge protein. This approach facilitates the polyubiquitination and subsequent degradation of BRD4/3/2 by the 26S proteasome. 9 effectively reduced the protein level of BRD4 short isoform in a time-, concentration-, GLP-, SPOP-, and ubiquitin-proteasome system (UPS)-dependent manner. Additionally, 9 effectively inhibited the proliferation of colorectal cancer (CRC) cells. Overall, our study expands the limited repertoire of the E3 ligases that can be harnessed for targeted protein degradation.

The voltage-gated potassium channel K_V7.2/3 is gaining attention for its association with several medical indications. While recently reported, potent compounds aimed to fill the therapeutic gap left by market-withdrawn activators, key physicochemical parameters did not meet the requirements of potential drug candidates. Targeting the membrane-located channel requires subtly balancing lipophilicity, activity, and aqueous solubility. This publication describes the lead optimization of a highly active compound toward optimized physicochemical parameters. Out of 42 newly synthesized compounds, 30 showed activity on K_V7.2/3 channels, and 15 had also an increased solubility compared the to hit compound. The integration of a three-dimensional bulky structure and the probable onset of chameleonic behavior, led to a 20-fold solubility increase (S = 21.7 vs 1.1 μM) and only slightly reduced potency (pEC₅₀ = 7.42 vs 7.96) for the lead. Additionally, the target engagement of the compound was theoretically enhanced by a reduction of membrane retention.