Novel potent inhibitors of the histone demethylase KDM1A (LSD1), orally active in a murine promyelocitic leukemia model.

Future Med Chem 2017 07 19;9(11):1161-1174. Epub 2017 Jul 19.

Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology, Ifom-IEO-Campus, via Adamello 16, 20139 Milan, Italy.

Background: Histone lysine demethylases (KDMs) are well-recognized targets in oncology drug discovery. They function at the post-translation level controlling chromatin conformation and gene transcription. KDM1A is a flavin adenine dinucleotide-dependent amine oxidase, overexpressed in several tumor types, including acute myeloid leukemia, neuroblastoma and non-small-cell lung cancer. Among the many known monoamine oxidase inhibitors screened for KDM1A inhibition, tranylcypromine emerged as a moderately active hit, which irreversibly binds to the flavin adenine dinucleotide cofactor.

Material & Methods: The KDM1A inhibitors 5a-w were synthesized and tested in vitro and in vivo. The biochemical potency was determined, modulation of target in cells was demonstrated on KDM1A-dependent genes and the anti-clonogenic activity was performed in murine acute promyelocytic Leukemia (APL) blasts. An in vivo efficacy experiment was conducted using an established murine promyelocytic leukemia model.

Results: We report a new series of tranylcypromine derivatives substituted on the cyclopropyl moiety, endowed with high potency in both biochemical and cellular assays.

Conclusion: The most interesting derivative (5a) significantly improved survival rate after oral administration in a murine model of promyelocitic leukemia.

Download full-text PDF

Source Listing
July 2017
Save 15% Survey

Similar Publications

Resurrection of Oral Arsenic Trioxide for Treating Acute Promyelocytic Leukaemia: A Historical Account From Bedside to Bench to Bedside.

Front Oncol 2020 4;10:1294. Epub 2020 Aug 4.

Department of Medicine, The University of Hong Kong, Hong Kong, China.

Various forms of arsenic were used in China and elsewhere for over 5,000 years. Following the initial success of intravenous arsenic trioxide (i.v. Read More

View Article and Full-Text PDF

Use of Minimal Residual Disease in Acute Myeloid Leukemia Therapy.

Curr Treat Options Oncol 2020 01 30;21(1). Epub 2020 Jan 30.

Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, Leipzig University Hospital, Liebigstrasse 22, Haus 7, 04103, Leipzig, Germany.

Opinion Statement: The expanding availability of minimal or more precisely measurable residual disease (MRD) assessment in acute myeloid leukemia (AML) with its possible implications for therapeutic decisions is of high interest to clinicians treating AML patients. A variety of mostly retrospective studies have shown that AML patients with a positive MRD test, assessed by different techniques at defined cutoffs and time-points, are at significantly higher risk of relapse and experience shorter overall survival compared to MRD-negative patients. How this valuable information may be adapted in the daily routine of patients' treatment to distinguish individuals who need more aggressive therapy from the ones who can be spared additional therapy to avoid treatment-related toxicities is still being investigated. Read More

View Article and Full-Text PDF
January 2020

HLA analysis of Mexican candidates for bone marrow transplantation and probability of finding compatible related donors.

Transfus Apher Sci 2018 Feb 3;57(1):82-87. Epub 2018 Jan 3.

Centro Nacional de la Transfusión Sanguínea, Av. Othón de Mendizábal 195, Zacatenco, Gustavo A. Madero, 07360, Mexico City, Mexico.

Introduction: Oncohematological disorders are the main cause of morbidity in the Mexican population from 1 to 19 years old, where megakaryoblastic and promyelocitic leukemias are more frequent. Considering that the success of a transplant is multifactorial, the criterion of compatibility in the HLA system is crucial and even more so when the source of HSC is bone marrow.

Objective: To determine the frequency of the HLA genotype in Mexican candidates who require a bone marrow transplant from related donors and the probability to find donors. Read More

View Article and Full-Text PDF
February 2018

Analysis of early death in newly diagnosed acute promyelocytic leukemia patients.

Medicine (Baltimore) 2017 Dec;96(51):e9324

Hematology Department, Nanfang Hospital, Southern Medical University, Guangzhou Hematology Department, Mianyang Central Hospital, Mianyang, China.

The aim of this study was to identify risk factors for early death (ED) in acute promyelocitic leukemia (APL) patients.Clinical records of 49 APL patients who suffered ED were divided into 4 groups: death before treatment or within the first 3 days (immediate death; iED group), death during treatment at least 3 days after commencement (ED after treatment), low/intermediate risk, and high-risk groups.White blood cell (WBC) count, high-risk cases, prothrombin time (PT) prolongation, international society on thrombosis and hemostasis (ISTH) scores (P < . Read More

View Article and Full-Text PDF
December 2017

Clinical characteristics and outcome of childhood acute promyelocitic leukemia (APL) in Saudi Arabia: a multicenter SAPHOS leukemia group study.

Hematology 2018 Jul 7;23(6):316-323. Epub 2017 Dec 7.

j Faculty of Medicine Alfaisal University , Riyadh , Saudi Arabia.

Background: Acute promyelocytic leukemia (APL) is a rare form of acute myelogenous leukemia (AML). Survival rates exceed 80% in developed countries. Successful treatments rely on all-trans retinoic acid with anthracycline-based chemotherapy. Read More

View Article and Full-Text PDF