Preclinical characterization of WB737, a potent and selective STAT3 inhibitor, in natural killer/T-cell lymphoma.
Preclinical characterization of WB737, a potent and selective STAT3 inhibitor, in natural killer/T-cell lymphoma.
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作者：
Wang, Yali;Zhou, Wenbo;Chen, Jianfeng;Chen, Jinghong;Deng, Peng;Chen, Huang;Sun, Yichen;Yu, Zhaoliang;Pang, Diwen;Liu, Lizhen;Wang, Peili;Hong, Jing Han;Teh, Bin Tean;Huang, Huiqiang;Li, Wenyu;Yi, Zhengfang;Lim, Soon Thye;Chen, Yihua;Ong, Choon Kiat;Liu, Mingyao;Tan, Jing
自然杀伤/T细胞淋巴瘤（NKTL）是一种罕见的恶性肿瘤，预后不良，治疗选择有限。NKTL患者中经常发现信号转导子和转录激活子3（STAT 3）的激活突变，这表明靶向抑制STAT 3是这种疾病的潜在治疗选择。在这里，我们开发了一种小分子药物WB 737，作为一种新型有效的STAT 3抑制剂，它以高亲和力直接结合STAT 3-Src同源2结构域。此外，WB 737与STAT 3的结合亲和力比STAT 1和STAT 2高250倍。有趣的是，与Stattic相比，WB 737在生长抑制和凋亡诱导方面对具有STAT 3激活突变的NKTL更具选择性。从机制上讲，WB 737通过抑制STAT 3分别在Tyr 705和Ser 727处的磷酸化来抑制经典和非经典STAT 3信号传导，从而抑制c-Myc和线粒体相关基因的表达。此外，WB 737比Stattic更有效地抑制STAT 3，导致显著的抗肿瘤作用，毒性不可检测，随后在携带STAT 3激活突变的NKTL异种移植模型中几乎完全肿瘤消退。综上所述，这些发现为WB 737作为一种新型治疗策略治疗具有STAT 3激活突变的NKTL患者提供了临床前概念验证。WB 737是一种新型的、有效的、选择性的STAT 3抑制剂。WB 737抑制pTyr 705-STAT 3的水平，从而抑制其转录活性。此外，WB 737还抑制pSer 727-STAT 3和编码电子传递链核心组分的基因的水平，从而损害呼吸复合物I活性，并导致氧化磷酸化的强烈抑制。
Natural killer/T‐cell lymphoma (NKTL) is an uncommon malignancy with poor prognosis and limited therapeutic options. Activating mutations of signal transducer and activator of transcription 3 (STAT3) are frequently found in patients with NKTL, suggesting that targeted inhibition of STAT3 is a potential therapeutic option for this disease. Here, we have developed a small molecule drug WB737 as a novel and potent STAT3 inhibitor that directly binds to the STAT3‐Src homology 2 domain with high affinity. In addition, the binding affinity of WB737 to STAT3 is 250‐fold higher than STAT1 and STAT2. Interestingly, WB737 is more selective for NKTL with STAT3‐activating mutations in terms of growth inhibition and apoptotic induction when compared with Stattic. Mechanistically, WB737 inhibits both canonical and noncanonical STAT3 signaling via suppression of STAT3 phosphorylation at Tyr705 and Ser727, respectively, thereby inhibiting the expression of c‐Myc and mitochondria‐related genes. Moreover, WB737 inhibited STAT3 more potently than Stattic, resulting in a significant antitumor effect with undetectable toxicity, followed by almost complete tumor regression in an NKTL xenograft model harboring a STAT3‐activating mutation. Taken together, these findings provide preclinical proof‐of‐concept for WB737 as a novel therapeutic strategy for the treatment of NKTL patients with STAT3‐activating mutations. WB737 is a novel, potent, and selective STAT3 inhibitor. WB737 suppresses the level of pTyr705‐STAT3, thereby inhibiting its transcriptional activity. In addition, WB737 also inhibits the levels of pSer727‐STAT3 and genes encoding core components of the electron transport chain, thereby impairing respiratory complex I activity and resulting in a strong inhibition of oxidative phosphorylation.