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

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 preclinical 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 downstream 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.

Emerging agents and regimens for AML

“…Given the proven synergies of BCL-2 inhibition, multiple combinations with targeted agents, and venetoclax are under investigation. There are many ongoing combinations of therapies targeting BCL-2 and other pathways, including FLT3 inhibitors (gilteritinib) and IDH1 and 2 inhibitors (Ivosidenib and enasidenib) (will be discussed in the later sections), MCL-1 inhibitors (VU661013, A-1210477); MEK1/2 inhibitor (cobimetinib), and MDM2 inhibitor (idasanutlin) (reviewed in [ 20 ]), combination with TKI in Ph + acute leukemia [ 21 ] and other emerging pre-clinical combinations including small-molecule inhibitors of CDK9 (the orally active A-1592668 and the related analog A-1467729) leading to down-expression of MCL-1 [ 22 ]; the Exportin inhibitor, Selinexor, [ 23 ]; BET inhibitors, ABBV-075, [ 24 ]; SRC family kinases (SFK) and Bruton's tyrosine kinase (BTK) inhibitor, ArQule 531 (ARQ 531), [ 25 ]; and it is expecting much more novel combinations to come.…”

Targeting Bcl-2 Proteins in Acute Myeloid Leukemia

“…These two pro-apoptotic proteins, NOXA and PUMA, can neutralize Mcl-1 to boost the activity of venetoclax ( 105 , 106 ). Ibrutinib, a Burton’s tyrosine kinase inhibitor, and ArQule 531, a multi-kinase inhibitor of Src family kinases and Burton’s tyrosine kinase, can also synergize with venetoclax ( 107 , 108 ). Pharmacologic inhibition of mitochondrial protein synthesis with antibiotics that target the ribosome, including tedizolid and doxycycline, can potently reverse venetoclax resistance.…”

Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia

“…Novel agents, including inhibitors of B-cell receptor signaling pathway (ibrutinib, acalabrutinib, idelalisib and duvelisib) and the inhibitor of the antiapoptotic protein BCL-2 (venetoclax), are superior compared to conventional chemoimmunotherapy (CIT) regimens. Cellular immunotherapy with chimeric antigen receptor T-cell (CAR-T) and allogeneic stem cell transplant (allo-SCT) are available for high-risk patients [3][4][5][6][7][8][9]. New challenges emerge when patients relapse on novel agents, and optimal sequencing strategies have not been established.…”