Abstract 2722: An added twist: drug-mediated pan-inhibition of KDM catalysis causes selective reduction of mRNAs that encode a small subset of KDM enzymes

作者：Hartmut Hanauske-Abel, M. Hoque, Seema Husain, Sukhwinder Singh, Axel-Rainer Hanauske, Patricia Soteropoulos · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/1538-7445.am2025-2722

The class of 2-oxoglutarate-requiring mono-iron dioxygenases (MIDOs) that demethylate specific lysine, histidine, or arginine residues of histones is receiving attention for its role in human diseases, in particular cancer (10.1016/j.ejmech.2022.114143). The steric events during MIDO catalysis were resolved at subatomic scale in 1982 by two students at Philipps University, Marburg/Germany (HAG mechanism [10.1016/0022-5193(82)90320-4, 10.1016/0022-5193(82)90320-4]). They presented a classification of all conceivable inhibitors and rapidly reduced their seminal approach to practice, establishing pyridine dicarboxylates and oxalylglycines as MIDO inhibitors, now in global use. In 1995, Cornell researchers employed HAG metrics to identify, among FDA-approved drugs, deferiprone (DFP) as MIDO inhibitor, enabling control of key protein families in vitro and in vivo (e.g. US-6080766-A). In 2019, DEF was identified as pan-selective inhibitor of histone lysine demethylating MIDOs (KDMs [10.1038/s41598-019-39214-1]). KDMs have, beyond their enzymatic activity, critical non-enzymatic functions in the physical assembly of the transcriptional machinery (10.3390/ijms25136900). We noted that DFP not only inhibits key MIDOs at clinically relevant serum concentrations, but also decreases selectively their encoding mRNAs, a precondition for reducing their biosynthesis. DEF not only inhibits KDM catalysis pan-selectively, but also reduces the biosynthesis of particular KDMs via knockdown ...