Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia
Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia
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DOI：
10.1186/s13045-019-0821-7
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发表时间：
2020-01-28
影响因子：
28.5
通讯作者：
Byrd, John C.
中科院分区：
文献类型：
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作者：
Elgamal, Ola A.;Mehmood, Abeera;Byrd, John C.
背景：急性髓系白血病（AML）是最常见的成人白血病类型。多项研究表明，AML的肿瘤发生可通过激酶信号通路增强，如Src家族激酶（SFK），包括Src和Lyn、脾酪氨酸激酶（SYK）和布鲁顿酪氨酸激酶（BTK）。最近，与不可逆的BTK抑制剂ibrutinib相比，多激酶抑制剂ArQule 531 （ARQ 531）在慢性淋巴细胞白血病（CLL）模型中表现出对SFK和BTK的有效抑制，转化为改善临床前体内活性。鉴于ARQ 531在CLL中的卓越活性，以及认识到该分子具有广泛的激酶抑制谱，我们寻求其在AML临床前模型中的应用。方法采用FLT3野生型和突变型AML细胞株及原代样品检测arq531的体外效价。arq531治疗后促生存激酶的调节是用AML细胞系测定的。通过SYK过表达细胞系（Ba/F3小鼠细胞）组成表达FLT3-ITD来评估SYK表达对ARQ 531效价的影响。最后，采用MOLM-13弥散性异种移植模型评价arq531的体内活性。结果我们的数据表明，ARQ 531治疗在体外具有抗增殖活性，并损害AML细胞系和原代AML细胞的集落形成，而不依赖FLT3 ITD突变的存在。我们发现ARQ 531靶向的致癌激酶，包括SFK （Tyr416）、BTK和fms相关酪氨酸激酶3 （FLT3）的磷酸化降低，最终导致下游靶标，包括SYK、STAT5a和ERK1/2的变化。基于体外药物协同作用数据，我们在MOLM-13 AML异种移植模型中单独和联合venetoclax检测了ARQ 531。尽管arq531在啮齿动物体内的药代动力学特征不太有利，但我们证明了适度的单药体内活性和与venetoclax的协同作用。结论：我们的数据支持考虑将ARQ 531应用于针对体内较高药物浓度的AML联合试验。
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.