TY - JOUR
T1 - Discovery of Reversible Inhibitors of KDM1A Efficacious in Acute Myeloid Leukemia Models
AU - Romussi, Alessia
AU - Cappa, Anna
AU - Vianello, Paola
AU - Brambillasca, Silvia
AU - Cera, Maria Rosaria
AU - Dal Zuffo, Roberto
AU - Fagà, Giovanni
AU - Fattori, Raimondo
AU - Moretti, Loris
AU - Trifirò, Paolo
AU - Villa, Manuela
AU - Vultaggio, Stefania
AU - Cecatiello, Valentina
AU - Pasqualato, Sebastiano
AU - Dondio, Giulio
AU - So, Chi Wai Eric
AU - Minucci, Saverio
AU - Sartori, Luca
AU - Varasi, Mario
AU - Mercurio, Ciro
N1 - Funding Information:
This work was supported by Rasna Therapeutics Inc.
Funding Information:
We are very grateful to Daniele Fancelli and Agostino Bruno (IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milano, Italy) for their helpful and valuable suggestions. We acknowledge the Paul Scherrer Institut, Villigen, Switzerland, and European Synchrotron Radiation Facility (ESRF) Grenoble, France, for provision of synchrotron radiation beamtime at beamline X06DA/PXIII of the SLS and ID30A-1/Massif-1 of the ESRF and thank the beamline scientists for their assistance. This work was supported by Rasna Therapeutics Inc.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/5/14
Y1 - 2020/5/14
N2 - Lysine-specific demethylase 1 (LSD1 or KDM1A) is a FAD-dependent enzyme that acts as a transcription corepressor or coactivator by regulating the methylation status of histone H3 lysines K4 and K9, respectively. KDM1A represents an attractive target for cancer therapy. While, in the past, the main medicinal chemistry strategy toward KDM1A inhibition was based on the optimization of ligands that irreversibly bind the FAD cofactor within the enzyme catalytic site, we and others have also identified reversible inhibitors. Herein we reported the discovery of 5-imidazolylthieno[3,2-b]pyrroles, a new series of KDM1A inhibitors endowed with picomolar inhibitory potency, active in cells and efficacious after oral administration in murine leukemia models.
AB - Lysine-specific demethylase 1 (LSD1 or KDM1A) is a FAD-dependent enzyme that acts as a transcription corepressor or coactivator by regulating the methylation status of histone H3 lysines K4 and K9, respectively. KDM1A represents an attractive target for cancer therapy. While, in the past, the main medicinal chemistry strategy toward KDM1A inhibition was based on the optimization of ligands that irreversibly bind the FAD cofactor within the enzyme catalytic site, we and others have also identified reversible inhibitors. Herein we reported the discovery of 5-imidazolylthieno[3,2-b]pyrroles, a new series of KDM1A inhibitors endowed with picomolar inhibitory potency, active in cells and efficacious after oral administration in murine leukemia models.
KW - epigenetics
KW - KDM1A
KW - leukemia
KW - LSD1
KW - lysine-specific demethylase-1
KW - Reversible inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85080067761&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85080067761&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.9b00604
DO - 10.1021/acsmedchemlett.9b00604
M3 - Article
AN - SCOPUS:85080067761
VL - 11
SP - 754
EP - 759
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 5
ER -