Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia

Mawar Karsa; Emma Ronca; Angelika Bongers; Anna Mariana; Ernest Moles; Timothy W Failes; Greg M Arndt; Laurence C Cheung; Rishi S Kotecha; Maria Kavallaris; Michelle Haber; Murray D Norris; Michelle J Henderson; Lin Xiao; Klaartje Somers

doi:10.3389/fonc.2021.779859

Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia

Front Oncol. 2022 Jan 20:11:779859. doi: 10.3389/fonc.2021.779859. eCollection 2021.

Authors

Mawar Karsa^{1

2}, Emma Ronca¹, Angelika Bongers¹, Anna Mariana^{1

3}, Ernest Moles^{1

2

4}, Timothy W Failes^{1

3}, Greg M Arndt^{1

2

3}, Laurence C Cheung^{5

6}, Rishi S Kotecha^{5

6

7

8}, Maria Kavallaris^{1

2

4}, Michelle Haber^{1

2}, Murray D Norris^{1

2

9}, Michelle J Henderson^{1

2}, Lin Xiao^{1

2}, Klaartje Somers^{1

2}

Affiliations

¹ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia.
² School of Women's and Children's Health, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia.
³ Australian Cancer Research Foundation (ACRF) Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia.
⁴ Australian Research Council (ARC) Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for Nanomedicine, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia.
⁵ Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia.
⁶ Curtin Medical School, Curtin University, Perth, WA, Australia.
⁷ Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children's Hospital, Perth, WA, Australia.
⁸ Division of Paediatrics, School of Medicine, University of Western Australia, Perth, WA, Australia.
⁹ University of New South Wales (UNSW) Centre for Childhood Cancer Research, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia.

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.

Keywords: KMT2A/MLL-rearranged leukemia; NR5A1; apoptosis; high-throughput screen; infant leukemia; repurposing.