Journal of Medicinal Chemistry最新文献

Photodynamic therapy (PDT) offers minimally invasive and repeatable cancer treatment options. Despite advancements in photosensitizer (PS) design, the optical control of PS activation remains unexplored. Here, we present the first photoswitchable PS based on a BOAHY-BODIPY dyad system. Inspired by BODIPY multimer structures and BOAHY's photoisomerization properties, we designed mono-(4 series) and bis-BOAHY-BODIPY (5 series) conjugates. These dyads primarily generate reactive oxygen species via a type-I process under white light. Notably, the 4 series compounds demonstrated effective photocytotoxicity and photoswitching properties in vitro. Building on these, we iodinated the monoconjugates to develop the highly efficient photoswitching PS, 6b, which exhibited enhanced intersystem crossing and type-II reactive oxygen species generation due to a reduced singlet-triplet energy gap. As the first demonstration of photoswitchable PDT agents, this strategy introduces a new approach with significant potential for selective cancer treatment and clinical applications.

METTL3 is the RNA methyltransferase predominantly responsible for the addition of N⁶-methyladenosine (m⁶A), the most abundant modification to mRNA. The prevalence of m⁶A and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML), thereby making METTL3 an attractive target for cancer therapeutics. We report herein the discovery and optimization of small-molecule inhibitors of METTL3, culminating in the selection of EP652 as an in vivo proof-of-concept compound. EP652 potently inhibits the enzymatic activity of METTL3, has favorable PK parameters, and demonstrates efficacy in preclinical oncology models, indicating that pharmacological inhibition of METTL3 is a viable strategy for the treatment of liquid and solid tumors.

In humans, the 2-oxoglutarate-dependent dioxygenases (2-OGDDs) catalyze hydroxylation reactions involved in cell metabolism, the biosynthesis of small molecules, DNA and RNA demethylation, the hypoxic response and the formation of collagen. The reaction is catalyzed by a highly oxidizing ferryl-oxo species produced when the active site non-heme iron engages molecular oxygen. Enzyme activity is specifically stimulated by l-ascorbic acid (ascorbate, vitamin C), an effect not well mimicked by other reducing agents. In this perspective article we discuss the reliance of the 2-OGDDs on ascorbate availability. We draw upon findings from studies with different 2-OGDDs to piece together a comprehensive theory for the specific role of ascorbate in supporting enzyme activity. Our discussion centers on the capacity for ascorbate to act as an efficient radical scavenger and its propensity to reduce and chelate transition metals. In addition, we consider the evidence supporting stereospecific binding of ascorbate in the enzyme active site.

A highly selective ferroptosis inducer with drug-like properties can significantly advance the research on inducing ferroptosis for anticancer treatment. We previously reported a highly active GPX4 inhibitor 26a, but its activity and stability need further improvement. In this work, a novel GPX4 inhibitor (R)-9i with more potent cytotoxicity (IC₅₀ = 0.0003 μM against HT1080) and ferroptosis selectivity (selectivity index = 24933) was gained via further electrophilic warhead screening and structure-based optimization. The cellular thermal shift assay (CETSA) indicated that (R)-9i could stabilize GPX4 with a T_m value of 6.2 °C. Furthermore, (R)-9i showed strong binding affinity against GPX4 (K_D = 20.4 nM). More importantly, (R)-9i has more favorable pharmacokinetic properties than 26a, which endowed (R)-9i with potential in antitumor research and as a tool drug for further study of ferroptosis. Associated with these, (R)-9i treatment significantly inhibited tumor growth in the xenograft tumor mouse model without detectable toxicity.