Abstract
Patients whose leukemias harbor a rearrangement of the Mixed Lineage Leukemia (MLL/KMT2A) gene have a poor prognosis, especially when the disease strikes in infants. The poor clinical outcome linked to this aggressive disease and the detrimental treatment side-effects, particularly in children, warrant the urgent development of more effective and cancer-selective therapeutics. The aim of this study was to identify novel candidate compounds that selectively target KMT2A-rearranged (KMT2A-r) leukemia cells. A library containing 3707 approved drugs and pharmacologically active compounds was screened for differential activity against KMT2A-r leukemia cell lines versus KMT2A-wild type (KMT2A-wt) leukemia cell lines, solid tumor cells and non-malignant cells by cell-based viability assays. The screen yielded SID7969543, an inhibitor of transcription factor Nuclear Receptor Subfamily 5 Group A Member 1 (NR5A1), that limited the viability of 7 out of 11 KMT2A-r leukemia cell lines including 5 out of 7 lines derived from infants, without affecting KMT2A-wt leukemia cells, solid cancer lines, non-malignant cell lines, or peripheral blood mononuclear cells from healthy controls. The compound also significantly inhibited growth of leukemia cell lines with a CALM-AF10 translocation, which defines a highly aggressive leukemia subtype that shares common underlying leukemogenic mechanisms with KMT2A-r leukemia. SID7969543 decreased KMT2A-r leukemia cell viability by inducing caspase-dependent apoptosis within hours of treatment and demonstrated synergy with established chemotherapeutics used in the treatment of high-risk leukemia. Thus, SID7969543 represents a novel candidate agent with selective activity against CALM-AF10 translocated and KMT2A-r leukemias that warrants further investigation.
Highlights
The conventional drug discovery path involves several drug development stages, from compound discovery, through to extensive preclinical drug optimization and characterization, which includes Absorption, Distribution, Metabolism, Elimination and Toxicity (ADMET) and efficacy studies in animal models, culminating in rigorous testing in humans through clinical trials
The library, consisting of the Prestwick (n=1200), Tocris (n=1119), LOPAC (n=1280) and Selleck (n=108) libraries, comprised a mixture of drugs approved by the FDA and other agencies, such as the European Medicines Agency, and biologically active compounds that cover a wide range of targets including kinases, neurotransmitter receptors and G-protein-coupled receptors
The library was screened against a KMT2A-r leukemia cell line, PER-485, harboring the most common KMT2A translocation found in infants and pediatric patients [t(4;11)], and a KMT2A-wt leukemia cell line CCRF-CEM [9, 12, 13]
Summary
The conventional drug discovery path involves several drug development stages, from compound discovery, through to extensive preclinical drug optimization and characterization, which includes Absorption, Distribution, Metabolism, Elimination and Toxicity (ADMET) and efficacy studies in animal models, culminating in rigorous testing in humans through clinical trials. Due to this time-consuming process, it has typically taken more than a decade for new agents to advance from bench to bedside, with the vast majority of compounds failing to reach the final stages of clinical trial testing. More potent and safer treatment options for KMT2A-r leukemia, for infant KMT2A-r ALL, are urgently needed
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