Polymyxins and quinazolines are LSD1/KDM1A inhibitors with unusual structural features.
Because of its involvement in the progression of several malignant tumors, the histone lysine-specific demethylase 1 (LSD1) has become a prominent drug target in modern medicinal chemistry research. We report on the discovery of two classes of noncovalent inhibitors displaying unique structural features. The antibiotics polymyxins bind at the entrance of the substrate cleft, where their highly charged cyclic moiety interacts with a cluster of positively charged amino acids. The same site is occupied by quinazoline-based compounds, which were found to inhibit the enzyme through a most peculiar mode because they form a pile of five to seven molecules that obstruct access to the active center. These data significantly indicate unpredictable strategies for the development of epigenetic inhibitors.
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
Valentina
0000-0002-7219-3097
V
Speranzini
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.
Dante
D
Rotili
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
Giuseppe
G
Ciossani
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
Simona
S
Pilotto
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
Biagina
B
Marrocco
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.; Center for Life Nano Science@Sapienza, Italian Institute of Technology, Viale Regina Elena 291, 00161 Rome, Italy.
Mariantonietta
0000-0002-0247-3712
M
Forgione
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.
Alessia
0000-0002-5113-4477
A
Lucidi
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
Federico
0000-0002-7818-1804
F
Forneris
Department of Experimental Oncology, European Institute of Oncology, via Adamello 16, 20139 Milan, Italy.
Parinaz
0000-0002-4476-9925
P
Mehdipour
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, Cambridgeshire CB10 1SD, U.K.
Sameer
0000-0002-8439-5964
S
Velankar
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.; Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.
Antonello
A
Mai
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
Andrea
0000-0002-9523-7128
A
Mattevi
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D057890:Epigenomics; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011113:Polymyxins / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D011113:Polymyxins; D011799:Quinazolines; D056466:Histone Demethylases; C495195:KDM1A protein, human
LSD1; histone demethylation; polymyxin; quinazoline; reversible inhibition