Reference Detail

Ref Type

Journal Article

PMID

(31992353)

Authors

Elgamal OA, Mehmood A, Jeon JY, Carmichael B, Lehman A, Orwick SJ, Truxall J, Goettl VM, Wasmuth R, Tran M, Mitchell S, Lapalombella R, Eathiraj S, Schwartz B, Stegmaier K, Baker SD, Hertlein E, Byrd JC

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of hematology & oncology	13	1	2020 Jan 28	8	J Hematol Oncol

URL

Abstract Text

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.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.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.Our data support consideration of the application of ARQ 531 in combination trials for AML targeting higher drug concentrations in vivo.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
ARQ 531	ARQ 531	1	4

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
ARQ 531		ARQ531\|ARQ-531\|Nemtabrutinib\|MK-1026\|MK 1026\|MK1026	BTK inhibitor 36	ARQ 531 is an ATP-competitive BTK inhibitor with activity against wild-type BTK and BTK C481S, which may inhibit migration and viability of tumor cells (PMID: 30093506, PMID: 31992353).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Entospletinib	Preclinical - Cell culture	Actionable	In a preclinical study, Entospletinib (GS-9973) treatment inhibited proliferation of acute myeloid leukemia cells harboring a FLT3-ITD in culture (PMID: 31992353).	31992353
FLT3 exon 14 ins	acute myeloid leukemia	not predictive	ARQ 531	Preclinical - Patient cell culture	Actionable	In a preclinical study, ARQ 531 treatment induced apoptosis in acute myeloid leukemia cells harboring either FLT3 exon 14 insertion (FLT3-ITD) or wild-type FLT3, and inhibited proliferation and reduced colony formation in patient cells derived from acute myeloid leukemia independent of FLT3 status in culture (PMID: 31992353).	31992353