2. Academic Validation
  3. Novel non-covalent LSD1 inhibitors endowed with anticancer effects in leukemia and solid tumor cellular models

Novel non-covalent LSD1 inhibitors endowed with anticancer effects in leukemia and solid tumor cellular models

  • Eur J Med Chem. 2022 Jul 5;237:114410. doi: 10.1016/j.ejmech.2022.114410.
Martina Menna 1,  Francesco Fiorentino 1,  Biagina Marrocco 2,  Alessia Lucidi 1,  Stefano Tomassi 3,  Domenica Cilli 4,  Mauro Romanenghi 4,  Matteo Cassandri 5,  Silvia Pomella 5,  Michele Pezzella 5,  Donatella Del Bufalo 6,  Mohammad Salik Zeya Ansari 7,  Nevena Tomašević 8,  Milan Mladenović 8,  Monica Viviano 9,  Gianluca Sbardella 9,  Rossella Rota 5,  Daniela Trisciuoglio 10,  Saverio Minucci 11,  Andrea Mattevi 2,  Dante Rotili 12,  Antonello Mai 13
Affiliations

Affiliations

  • 1 Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy.
  • 2 Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100, Pavia, Italy.
  • 3 Department of Pharmacy, University of Naples "Federico II", via Domenico Montesano 49, 80131, Naples, Italy.
  • 4 Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, via Adamello 16, 20139, Milan, Italy.
  • 5 Department of Oncohematology, Bambino Gesù Children's Hospital, IRCCS, viale di San Paolo 15, 00146, Rome, Italy.
  • 6 Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
  • 7 Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy; Institute of Molecular Biology and Pathology, National Research Council (CNR), Via degli Apuli 4, 00185, Rome, Italy.
  • 8 Kragujevac Center for Computational Biochemistry, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000, Kragujevac, P.O. Box 60, Serbia.
  • 9 Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy.
  • 10 Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy; Institute of Molecular Biology and Pathology, National Research Council (CNR), Via degli Apuli 4, 00185, Rome, Italy.
  • 11 Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, via Adamello 16, 20139, Milan, Italy; Department of Biosciences, University of Milan, Via Festa del Perdono 7, 20122, Milano, Italy.
  • 12 Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy. Electronic address: dante.rotili@uniroma1.it.
  • 13 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. Electronic address: antonello.mai@uniroma1.it.
PMID: 35525212 DOI: 10.1016/j.ejmech.2022.114410
Abstract

LSD1 is a histone lysine demethylase proposed as therapeutic target in Cancer. Chemical modifications applied at C2, C4 and/or C7 positions of the quinazoline core of the previously reported dual LSD1/G9a inhibitor 1 led to a series of non-covalent, highly active, and selective LSD1 inhibitors (2-4 and 6-30) and to the dual LSD1/G9a inhibitor 5 that was more potent than 1 against LSD1. In THP-1 and MV4-11 leukemic cells, the most potent compounds (7, 8, and 29) showed antiproliferative effects at sub-micromolar level without significant toxicity at 1 μM in non-cancer AHH-1 cells. In MV4-11 cells, the new derivatives increased the levels of the LSD1 histone mark H3K4me2 and induced the re-expression of the CD86 gene silenced by LSD1, thereby confirming the inhibition of LSD1 at cellular level. In breast MDA-MB-231 as well as in rhabdomyosarcoma RD and RH30 cells, taken as examples of solid tumors, the same compounds displayed cell growth arrest in the same IC50 range, highlighting a crucial Anticancer role for LSD1 inhibition and suggesting no added value for the simultaneous G9a inhibition in these tumor cell lines.

Keywords

Cancer; Drug discovery; Histone lysine methyltransferases; Lysine-specific demethylase 1; Polypharmacology.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z