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
State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer Medicine Sun Yat-Sen University Cancer Center Guangzhou China.
Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai China.
MedComm (2020). 2023 Jun 16;4(4):e284. doi: 10.1002/mco2.284. eCollection 2023 Aug.
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 -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 -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 -activating mutations.
自然杀伤/T细胞淋巴瘤（NKTL）是一种罕见的恶性肿瘤，预后较差且治疗选择有限。信号转导及转录激活因子3（STAT3）的激活突变在NKTL患者中经常被发现，这表明靶向抑制STAT3是该疾病的一种潜在治疗选择。在此，我们开发了一种小分子药物WB737，作为一种新型强效的STAT3抑制剂，它能以高亲和力直接结合到STAT3的Src同源2结构域。此外，WB737与STAT3的结合亲和力比STAT1和STAT2高250倍。有趣的是，与Stattic相比，WB737在生长抑制和诱导凋亡方面对具有激活突变的NKTL更具选择性。从机制上讲，WB737分别通过抑制Tyr705和Ser727位点的STAT3磷酸化来抑制经典和非经典的STAT3信号通路，从而抑制c-Myc和线粒体相关基因的表达。此外，WB737比Stattic更有效地抑制STAT3，在具有激活突变的NKTL异种移植模型中产生了显著的抗肿瘤作用且毒性不可检测，随后肿瘤几乎完全消退。综上所述，这些发现为WB737作为治疗具有激活突变的NKTL患者的一种新型治疗策略提供了临床前概念验证。
