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15. Alessia Lucidi

Sapienza University of Rome
Structural manipulations of the quinazoline scaffold can alternatively determine the dual G9a methyltransferase/LSD1 demethylase inhibitory activity or the selective inhibition of LSD1.
Rome, Italy
In humans, histone methylation pattern results from the balance between lysine methylation and demethylation. The removal of methyl unit(s) is performed by two families of demethylases (KDMs) that differ for the reaction mechanism, one being FAD-dependent amine oxidases (LSD1/2) and the others being iron/α-ketoglutarate dependent proteins (JmJC)1. LSD1 is able to remove methyl groups from H3K4me1/2 marks and, in association with the co-repressor protein Co-REST, is part of a multicomponent repressive complex including also REST and HDAC1/22. LSD1 plays a crucial role in the epigenetic modulation of gene expression and represents a valuable target in cancer chemotherapy, since it is overexpressed in several types of tumors3. Our investigation of quinazolines as H3K9 methyltransferase/demethylase or DNMT inhibitors led us to identify MC3774, a Lys-mimicking derivative displaying dual G9a methyltransferase/LSD1 inhibition showing IC50 values of 1205 nM and 440 nM on G9a and LSD1 respectively. In MV4-11 leukemia cells, MC3774 displayed antiproliferative activity with IC50=894 nM. The most interesting aspect of this investigation is about the inhibition mechanism. While MC3774 interacts with G9a in a classical way inside the binding pocket of the enzyme, in LSD1 it is located stacking five copies of itself and obstructing in this way the active site. The orientation of the molecules can be “face to face” or “head to tail”, and in both modes they interact with a cluster of negatively charged aminoacidic residues4. Considering these observation, we worked on the synthesis of several analogs of the lead compound MC3774, modifying the quinazoline scaffold in position 2 with alkylamino functions of different length variously substituted at omega position and replacing the NH in position 4 with an oxygen atom or with N-CH3, or modifying the N-benzyl moiety with other aryl-alkyl functions, with the aim to investigate the structure activity relationship for the dual activity or for selective inhibition of LSD1 and to improve the potency of compounds in AML cells. The results are consistent with the inhibition mechanism. In fact, the insertion, on different position, of electron-rich functions, increase the potency on LSD1 and the disguise of proton donor groups determines the loss of the inhibitory activity on G9a. References 1. Rotili, D., Mai, A., Genes & Cancer 2011, 2, 663-679. 2.Saleque, S., Kim, J., Rooke, H.M., Orkin, S.H. Mol. Cell. 2007, 27, 562-572. 3. Hojfeldt, J. W., Agger, K., Helin, K. Nat. Rev. Drug Discov., 2013, 12, 917-930. 4. Speranzini et al., Science Advance, 2016, vol 2, 9.