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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2020

Open Access 01-12-2020 | Chronic Lymphocytic Leukemia | Research

Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia

Authors: Ola A. Elgamal, Abeera Mehmood, Jae Yoon Jeon, Bridget Carmichael, Amy Lehman, Shelley J. Orwick, Jean Truxall, Virginia M. Goettl, Ronni Wasmuth, Minh Tran, Shaneice Mitchell, Rosa Lapalombella, Sudharshan Eathiraj, Brian Schwartz, Kimberly Stegmaier, Sharyn D. Baker, Erin Hertlein, John C. Byrd

Published in: Journal of Hematology & Oncology | Issue 1/2020

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Abstract

Background

Acute myeloid leukemia (AML) is the most common type of adult leukemia. Several studies have demonstrated that oncogenesis in AML is enhanced by kinase signaling pathways such as Src family kinases (SFK) including Src and Lyn, spleen tyrosine kinase (SYK), and bruton’s tyrosine kinase (BTK). Recently, the multi-kinase inhibitor ArQule 531 (ARQ 531) has demonstrated potent inhibition of SFK and BTK that translated to improved pre-clinical in vivo activity as compared with the irreversible BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) models. Given the superior activity of ARQ 531 in CLL, and recognition that this molecule has a broad kinase inhibition profile, we pursued its application in pre-clinical models of AML.

Methods

The potency of ARQ 531 was examined in vitro using FLT3 wild type and mutated (ITD) AML cell lines and primary samples. The modulation of pro-survival kinases following ARQ 531 treatment was determined using AML cell lines. The effect of SYK expression on ARQ 531 potency was evaluated using a SYK overexpressing cell line (Ba/F3 murine cells) constitutively expressing FLT3-ITD. Finally, the in vivo activity of ARQ 531 was evaluated using MOLM-13 disseminated xenograft model.

Results

Our data demonstrate that ARQ 531 treatment has anti-proliferative activity in vitro and impairs colony formation in AML cell lines and primary AML cells independent of the presence of a FLT3 ITD mutation. We demonstrate decreased phosphorylation of oncogenic kinases targeted by ARQ 531, including SFK (Tyr416), BTK, and fms-related tyrosine kinase 3 (FLT3), ultimately leading to changes in down-stream targets including SYK, STAT5a, and ERK1/2. Based upon in vitro drug synergy data, we examined ARQ 531 in the MOLM-13 AML xenograft model alone and in combination with venetoclax. Despite ARQ 531 having a less favorable pharmacokinetics profile in rodents, we demonstrate modest single agent in vivo activity and synergy with venetoclax.

Conclusions

Our data support consideration of the application of ARQ 531 in combination trials for AML targeting higher drug concentrations in vivo.
Appendix
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Metadata
Title
Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia
Authors
Ola A. Elgamal
Abeera Mehmood
Jae Yoon Jeon
Bridget Carmichael
Amy Lehman
Shelley J. Orwick
Jean Truxall
Virginia M. Goettl
Ronni Wasmuth
Minh Tran
Shaneice Mitchell
Rosa Lapalombella
Sudharshan Eathiraj
Brian Schwartz
Kimberly Stegmaier
Sharyn D. Baker
Erin Hertlein
John C. Byrd
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2020
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-019-0821-7

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