Unravelling KDM4 histone demethylase inhibitors for cancer therapy

Transcriptomic and Drug Discovery Analyses Reveal Natural Compounds Targeting the KDM4 Subfamily as Promising Adjuvant Treatments in Cancer

“…We analyzed 15 representative clusters, arbitrarily numbered, while isolated nodes (436 out of the 1,500 compounds evaluated) represent ligands with no similar molecules according to the criteria used ( Figure 4A ). In the literature had been reported molecules experimentally validated as inhibitors of the KDM4 subfamily; thus, for the flexophore analysis, we included 16 compounds cited by ( Baby et al, 2021 ) whose IC50 is of micro to nanomolar range (nodes in bold in Figure 4A ). We observed that most of these molecules remained as isolated nodes whose floxophores did not share similarities with the compounds from COCONUT, DrugBank, and FDA databases.…”

“…In this sense, it is relevant that a specific binding mechanism with a competitive inhibitor is established for one or some KDM4 proteins. In fact, most of the KDM4 inhibitors reported are known to target other KDMs which limits their use for cancer treatment ( Chin and Han, 2015 ; Baby et al, 2021 ). Furthermore, we showed that the KDM4 subfamily’s expression is heterogeneous among different cancer types, which adds another layer of complexity to the search for inhibitor molecules that could favor the treatment of neoplasms where the KDM4 proteins are relevant.…”

“…Since the KDM4 subfamily is a promising therapeutic target for drug design, a wide number of synthetic and nature-inspired molecules have been explored. Among them, it has been proposed that catechol and flavonoids as structural scaffolds, these kinds of molecules have gained attention because of their high content of OH with redox capacity that can also act as free radical regulators ( Baby et al, 2021 ). Such functional groups can favor their interaction with high electronegative residues located in the active site of KDM4 proteins, as shown in this study.…”

“…As shown in this work the identified molecules could have an amplified therapeutic effect by modulating, not only KDM4 functions but entire cellular processes, by modifying the activity of proteins involved in the same pathways. This mechanism of action has been proposed for other diseases and protein targets before ( Cheng et al, 2019 ); however, the study of KDM4 inhibitors remains approached without considering the molecular context required for their proper function ( Chin and Han, 2015 ; Baby et al, 2021 ). Overall, our data suggest that natural compounds could be used as adjuvant therapies in cancer, which opens a new window of opportunities for the search of KDM4 subfamily inhibitors and contributes to the search of novel cancer therapies.…”

“…For example, disulfiram and ebselen are metal cofactor disruptors that inhibit KDM4A through the obstruction of the Zn 2+ ion at its catalytic site; however, those drugs target other zinc-binding proteins as well, including other KDMs ( Rotili and Mai, 2011 ). Other known KDM4A inhibitors are 2-oxoglutarate analogs, these molecules act as competitive inhibitors but, since 2-oxoglutarate is a cofactor for several other enzymes including all the JMJC family, these molecules have low specificity ( Baby et al, 2021 ). Because there are cancer types that show dysregulation of only one family member ( Sterling et al, 2020 ), it is important to achieve specific and effective inhibitors for each enzyme.…”