Abstract
Background: LSD-1 is an enzyme that removes methyl groups from lysine residues of histone proteins. LSD-1 inhibition decreases cellular proliferation and therefore represents a therapeutic target for cancer treatment. MAO and LSD-1 are both flavin adenine dinucleotide-dependent MAOs, and the MAO inhibitor, tranylcypromine, is currently undergoing clinical trials for cancer treatment because it acts as an irreversible LSD-1 inhibitor. Materials & methods: The present study investigated new reversible LSD-1 inhibitors, in order to develop novel selective anticancer agents. We constructed 2 and 3D quantitative structure–activity relationship models by using a series of 54 aminothiazole and thiazolesulfonamide derivatives. Results: The models were validated internally and externally (q2, 0.691 and 0.701; r2, 0.894 and 0.937; r2test, 0.785 and 0.644, for 2 and 3D models, respectively). Fragment contribution maps, as well as steric and electrostatic contour maps were generated in order to obtain chemical information related to LSD-1 inhibition. Conclusion: The thiazolesulfonamide group was fundamental to the inhibition of LSD-1 by these compounds and that bulky and aromatic substituents at the thiazole ring were important for their steric and electrostatic interactions with the active site of LSD-1.
Financial & competing interests disclosure
The authors would like to thank CAPES (Special Visiting Researcher 119/2012), grant #2012/20990-2, São Paulo Research Foundation (FAPESP) and CNPq (312009/2014-3 and 477002/2013-7) for financial support and also OpenEye Scientific Software for OMEGA and ROCS academic licenses. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
English language editing was provided by EDITAGE and funded by grant #2012/20990-2.