Related Experiment Video
Updated: Jul 21, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP
Yongsheng Xie1, Yingcong Wang1, Zhijian Xu2
1Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 YanChang Road, Shanghai, 200072, China.
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.
Insights
A novel drug, 4-hydroxysalicylanilide (HDS), inhibits Ribonucleotide reductase (RNR) to disrupt DNA repair in multiple myeloma (MM). HDS shows promise as a new therapeutic agent for MM patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Aberrant DNA repair pathways are implicated in multiple myeloma (MM) pathogenesis, progression, and drug resistance.
- Ribonucleotide reductase (RNR) is a key enzyme in deoxyribonucleotide (dNTP) synthesis, crucial for DNA replication and repair.
- Targeting RNR presents a potential therapeutic strategy for MM.
Purpose of the Study:
- To investigate the efficacy of the novel RNR inhibitor, 4-hydroxysalicylanilide (HDS), in preclinical models of multiple myeloma (MM).
- To assess the clinical activity and safety of HDS in patients diagnosed with MM.
Main Methods:
- Utilized bioinformatic, genetic, and pharmacological approaches to confirm HDS as a direct inhibitor of RNR subunit M2 (RRM2).
- Evaluated HDS activity alone and in synergy with standard treatments in vitro and in vivo.
- Conducted a Phase I clinical trial (ClinicalTrials.gov: NCT03670173) to assess the safety and efficacy of single-agent HDS in MM patients.
Main Results:
- HDS directly inhibited RNR by targeting RRM2, decreasing dNTP synthesis and DNA repair.
- This led to the accumulation of DNA double-strand breaks, inhibiting MM cell proliferation and inducing apoptosis.
- HDS demonstrated efficacy in a MM xenograft model, overcame protective effects of microenvironment factors, and showed synergistic activity with melphalan and bortezomib.
- The drug exhibited a favorable safety profile and clinical activity in MM patients.
Conclusions:
- HDS effectively targets RNR and exhibits anti-myeloma activity by inducing DNA damage.
- The drug shows potential as a therapeutic agent for MM, both as a monotherapy and in combination regimens.
- Clinical evaluation of HDS is warranted for the treatment of multiple myeloma.
More Related Videos
Related Concept Videos
01:27Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase