Discovery of Potent and Selective MNK Kinase Inhibitors for the Treatment of Leukemia

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

MNK activity is regulated by the p38 and Erk MAPK pathways. Phosphorylation of leads to its activation binding eIF4G/eIF4E complex. then phosphorylates eIF4E at Ser209, whose associated with oncogene translation, leading tumorigenesis. Given this important role for in tumorigenesis, inhibition novel small molecule inhibitors could be a promising strategy combat AML, which continues an area unmet medical need. Here, we report medicinal optimization series their evaluation effects on leukemia cell viability. We discovered class ether-containing compounds high MNK1/2 selectivity. These show good potency reducing viability colony formation have desirable pharmacokinetic properties. X-ray cocrystallization was accomplished confirm mode our aid future optimization.

Language: Английский

---

Rare Chlorinated C₁₉ Steroids Hocarnoids A and B from Hoya carnosa: Isolation, Semisynthesis, and Anti-inflammation

The Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Steroids have consistently drawn scientific attention due to their diverse structures and exceptional pharmacological activities. However, halogenated natural steroids remain relatively rare, especially for those derived from plants. In this study, two chlorinated C19 hocarnoids A (1) B (2) were identified the folk medicinal plant Hoya carnosa, representing first examples of C-16 steroids. Semisynthesis compounds 1 2 was completed in 4 5 linear steps with 28.2% 25.3% overall yields through a modified approach, corroborating further structures. total collection 11 steroids, including intermediates obtained during synthesis, evaluated anti-inflammatory activity against lipopolysaccharide (LPS)-induced inflammation-related RAW 264.7 macrophages. Among them, product hocarnoid displayed strongest an IC50 value 3.62 ± 0.08 μM, which also attenuated mRNA levels proinflammatory cytokines IL-1β, IL-6, IL-10, TNF-α.

Language: Английский

---

Design, Synthesis, and Evaluation of Novel ROCK Inhibitors for Glaucoma Treatment: Insights into In Vitro and In Vivo Efficacy and Safety

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: May 8, 2025

The inhibition of Rho-associated coiled-coil kinase (ROCK) has emerged as a promising strategy for reducing intraocular pressure (IOP) and treating glaucoma. Here, we report the synthesis evaluation novel ROCK inhibitors, D25 R3, which were designed to optimize selectivity, efficacy, ocular bioavailability. potently inhibited ROCK1/2 with IC50 values 47.2 nM 33.8 nM, respectively, surpassing Netarsudil. Compound R3 had weaker but demonstrated favorable lipophilicity (logP) good selectivity ROCKs, enhances its potential safety delivery. In human trabecular meshwork (HTM) cells, showed lower cytotoxicity than Netarsudil effectively mitigated oxidative damage, enhanced cellular integrity, reduced inflammatory cytokine secretion. rabbit models, significantly lowered IOP, outperforming (S)-Netarsudil. exhibited IOP-lowering efficacy better selectivity. is glaucoma treatment candidate, safer alternative further optimization.

Language: Английский

---

A patent review of mitogen-activated protein kinase-interacting kinases (MNKs) modulators (2019-present)

Expert Opinion on Therapeutic Patents, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 21, 2024

The mitogen-activated protein kinase interacting kinases (MNKs) modulate translation through the phosphorylation of eukaryotic initiation factor 4E (eIF4E) at serine 209, which is crucial for tumorigenesis but dispensable normal development. MNKs are implicated in various pathological processes, including inflammation, obesity, cancer, etc. Thus, considered as potential drug targets and development potent selective MNK inhibitors a current research focus.

Language: Английский

---