The Novel Kinase Inhibitor PRT062070 (Cerdulatinib) Demonstrates Efficacy in Models of Autoimmunity and B-Cell Cancer
The Novel Kinase Inhibitor PRT062070 (Cerdulatinib) Demonstrates Efficacy in Models of Autoimmunity and B-Cell Cancer
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DOI：
10.1124/jpet.114.218164
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发表时间：
2014-12-01
影响因子：
3.5
通讯作者：
Sinha, Uma
中科院分区：
文献类型：
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作者：
Coffey, Greg;Betz, Andreas;Sinha, Uma
某些自身免疫性疾病和B细胞恶性肿瘤的异质性和严重性保证了多种疾病相关信号通路的同时靶向。脾酪氨酸激酶（SYK）和Janus激酶（JAK）的双重抑制代表了这样一种策略，相对于选择性激酶抑制，可能会产生几种益处，例如获得对更广泛疾病病因的控制，降低旁路疾病机制的选择概率，以及个体靶点的总体较低水平抑制可能足以调节疾病活动的潜力。为此，我们提供了PRT 062070 [4-（环丙基氨基）-2-（{4-[4-（乙基磺酰基）哌嗪-1-基]苯基}氨基）嘧啶-5-甲酰胺盐酸盐]的发现和临床前开发数据，这是一种口服活性激酶抑制剂，显示出对SYK和JAK的活性。细胞测定证明了对使用SYK和JAK 1/3的信号通路的特异性抑制活性。观察到对JAK 2的有限抑制，PRT 062070既不抑制B和T细胞中佛波醇12-肉豆蔻酸酯13-乙酸酯介导的信号传导或活化，也不抑制T细胞中T细胞抗原受体介导的信号传导，这为作用的选择性提供了证据。在B细胞淋巴瘤细胞系亚组中观察到有效的抗肿瘤活性。经口给药后，PRT 062070在大鼠胶原诱导的关节炎模型中抑制炎症和自身抗体产生，并在慢性B细胞抗原受体刺激的小鼠模型中阻断B细胞活化和脾肿大。PRT 062070目前正在B细胞白血病和淋巴瘤患者的I期剂量递增研究（NCT 01994382）中进行评估，计划在人体中进行概念验证研究，以评估自身免疫性和恶性疾病的治疗潜力。
The heterogeneity and severity of certain autoimmune diseases and B-cell malignancies warrant simultaneous targeting of multiple disease-relevant signaling pathways. Dual inhibition of spleen tyrosine kinase (SYK) and Janus kinase (JAK) represents such a strategy and may elicit several benefits relative to selective kinase inhibition, such as gaining control over a broader array of disease etiologies, reducing probability of selection for bypass disease mechanisms, and the potential that an overall lower level suppression of individual targets may be sufficient to modulate disease activity. To this end, we provide data on the discovery and preclinical development of PRT062070 [4-(cyclopropylamino)-2-({4-[4-(ethylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidine-5-carboxamide hydrochloride], an orally active kinase inhibitor that demonstrates activity against SYK and JAK. Cellular assays demonstrated specific inhibitory activity against signaling pathways that use SYK and JAK1/3. Limited inhibition of JAK2 was observed, and PRT062070 did not inhibit phorbol 12-myristate 13-acetate-mediated signaling or activation in B and T cells nor T-cell antigen receptor-mediated signaling in T cells, providing evidence for selectivity of action. Potent antitumor activity was observed in a subset of B-cell lymphoma cell lines. After oral dosing, PRT062070 suppressed inflammation and autoantibody generation in a rat collagen-induced arthritis model and blocked B-cell activation and splenomegaly in a mouse model of chronic B-cell antigen receptor stimulation. PRT062070 is currently under evaluation in a phase I dose escalation study in patients with B-cell leukemia and lymphoma (NCT01994382), with proof-of-concept studies in humans planned to assess therapeutic potential in autoimmune and malignant diseases.