Francesco Calzaferri (he/him) (@franczf.bsky.social)

A new tool for epigenetic reprogramming? 😎 We have finally found out how to increase our flavanones stability and obtain DNA methyltransferase inhibitors with nanomolar potency 🥳 pubs.acs.org/doi/full/10....

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Rational Design and Synthesis of Highly Stable Haloflavanone DNA Methyltransferase Inhibitors Inducing Tumor Suppressor Gene Re-expression in Cancer Cells DNA methylation is an epigenetic modification involved in cancer. The clinically approved nucleoside DNA methyltransferase (DNMT) inhibitors 5-azacytidine and 5-aza-2′-deoxycytidine lack selectivity and stability, resulting in high toxicity. Previously, we discovered 3-halo-3-nitroflavanones as non-nucleoside DNMT inhibitors. Here, we designed and synthesized a new series of 2-substituted haloflavanones to increase compound chemical stability. Moreover, replacement of the nitro by an additional halogen enhanced compound potency. Indeed, compound 34b (anti-3-bromo-3-chloro-2-methoxyflavanone) exhibited submicromolar DNMT3A inhibitory activity, upregulated the expression of DNMT-targeted genes, and impaired cell proliferation. Importantly, 34b triggered a critical cell cycle arrest in the G1/S transition, notably in p53-depleted HCT-116 colorectal cancer cells, which paves the way for novel therapeutic opportunities. 34b competes for the same DNMT catalytic pocket as confirmed by saturation transfer difference-nuclear magnetic resonance, but assuming different docking poses as shown by computational studies. Overall, the high stability and activity of 34b make it a promising DNMT inhibitor for anticancer research and therapy. https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.4c02075