靶向多骨髓瘤中核昔酸还原酶介导的 dNTP 合成的 4-轻基水杨酰苯胺的临床前验证和 I 期试验。
Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma.
机构信息
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China.
CAS Key Laboratory of Receptor Research; State Key Laboratory of Drug Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
出版信息
J Biomed Sci. 2022 May 12;29(1):32. doi: 10.1186/s12929-022-00813-2.
BACKGROUND
Aberrant DNA repair pathways contribute to malignant transformation or disease progression and the acquisition of drug resistance in multiple myeloma (MM); therefore, these pathways could be therapeutically exploited. Ribonucleotide reductase (RNR) is the rate-limiting enzyme for the biosynthesis of deoxyribonucleotides (dNTPs), which are essential for DNA replication and DNA damage repair. In this study, we explored the efficacy of the novel RNR inhibitor, 4-hydroxysalicylanilide (HDS), in myeloma cells and xenograft model. In addition, we assessed the clinical activity and safety of HDS in patients with MM.
METHODS
We applied bioinformatic, genetic, and pharmacological approaches to demonstrate that HDS was an RNR inhibitor that directly bound to RNR subunit M2 (RRM2). The activity of HDS alone or in synergy with standard treatments was evaluated in vitro and in vivo. We also initiated a phase I clinical trial of single-agent HDS in MM patients (ClinicalTrials.gov: NCT03670173) to assess safety and efficacy.
RESULTS
HDS inhibited the activity of RNR by directly targeting RRM2. HDS decreased the RNR-mediated dNTP synthesis and concomitantly inhibited DNA damage repair, resulting in the accumulation of endogenous unrepaired DNA double-strand breaks (DSBs), thus inhibiting MM cell proliferation and inducing apoptosis. Moreover, HDS overcame the protective effects of IL-6, IGF-1 and bone marrow stromal cells (BMSCs) on MM cells. HDS prolonged survival in a MM xenograft model and induced synergistic anti-myeloma activity in combination with melphalan and bortezomib. HDS also showed a favorable safety profile and demonstrated clinical activity against MM.
CONCLUSIONS
Our study provides a rationale for the clinical evaluation of HDS as an anti-myeloma agent, either alone or in combination with standard treatments for MM.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT03670173, Registered 12 September 2018.
背景
异常的 DNA 修复途径导致多发性骨髓瘤（MM）中的恶性转化或疾病进展以及获得耐药性；因此，这些途径可能具有治疗潜力。核酶还原酶（RNR）是脱氧核苷酸（dNTP）生物合成的限速酶，dNTP 对 DNA 复制和 DNA 损伤修复至关重要。在这项研究中，我们研究了新型 RNR 抑制剂 4-羟基水杨酰苯胺（HDS）在骨髓瘤细胞和异种移植模型中的疗效。此外，我们评估了 HDS 在 MM 患者中的临床活性和安全性。
方法
我们应用生物信息学、遗传和药理学方法证明 HDS 是一种 RNR 抑制剂，可直接与 RNR 亚基 M2（RRM2）结合。单独使用 HDS 或与标准治疗联合使用的活性在体外和体内进行了评估。我们还启动了一项 HDS 单药治疗 MM 患者的 I 期临床试验（ClinicalTrials.gov：NCT03670173），以评估安全性和疗效。
结果
HDS 通过直接靶向 RRM2 抑制 RNR 的活性。HDS 减少了 RNR 介导的 dNTP 合成，并同时抑制了 DNA 损伤修复，导致内源性未修复的 DNA 双链断裂（DSBs）积累，从而抑制了 MM 细胞的增殖并诱导细胞凋亡。此外，HDS 克服了 IL-6、IGF-1 和骨髓基质细胞（BMSCs）对 MM 细胞的保护作用。HDS 延长了 MM 异种移植模型的存活时间，并与美法仑和硼替佐米联合诱导协同抗骨髓瘤活性。HDS 还具有良好的安全性，并显示出对 MM 的临床活性。
结论
我们的研究为 HDS 作为抗骨髓瘤药物的临床评估提供了依据，无论是单独使用还是与 MM 的标准治疗联合使用。
试验注册
ClinicalTrials.gov，NCT03670173，2018 年 9 月 12 日注册。
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