Modulators of histone demethylase JMJD1C selectively target leukemic stem cells
Abstract
Leukemic stem cells (LSCs) comprise a very rare cell population that results in the development of acute myeloid leukemia. The selective targeting of drivers in LSCs with small molecule inhibitors holds promise for treatment of acute myeloid leukemia. Recently, we reported the identification of inhibitors of the histone lysine demethylase JMJD1C that preferentially kill MLL rearranged acute leukemia cells. Here, we report the identification of jumonji domain modulator #7 (JDM-7). Surface plasmon resonance analysis showed that JDM-7 binds to JMJD1C and its family homolog JMJD1B. JDM-7 did not significantly suppress cell proliferation in liquid cell culture at higher doses, although it led to a significant decrease in semi-solid colony formation experiments at lower concentrations. Moreover, low doses of JDM-7 did not suppress the proliferation of erythroid progenitor cells. We identified that JDM-7 downregulates the LSC self-renewal gene HOXA9 in leukemia cells. We further found that the structure of JDM-7 is similar to that of tadalafil, a drug approved by the US Food and Drug Administration. Molecular docking and surface plasmon resonance analysis showed that tadalafil binds to JMJD1C. Moreover, similar to JDM-7, tadalafil suppressed colony formation of leukemia cells in semi-solid cell culture at a concentration that did not affect primary umbilical cord blood cells. In summary, we have identified JDM-7 and tadalafil as potential JMJD1C modulators that selectively inhibit…
Read the paper
Related studies
- Protective effects of tadalafil and N-acetyl cysteine therapy on cisplatin-induced testicular toxicity
- The Use of Generative AI for Scientific Literature Searches for Systematic Reviews: ChatGPT and Microsoft Bing AI Performance Evaluation
- Sildenafil as a Candidate Drug for Alzheimer’s Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons
- Ozone-modified properties of pumpkin seed oil as anti-H. pylori, anticancer, anti-diabetic and anti-obesity agent
- Effectiveness of Low-Intensity Extracorporeal Shock Wave Therapy in Erectile Dysfunction: An Analysis of Sexual Function and Penile Hardness at Erection: An Umbrella Review
- Molecular Docking of Silymarin as a Ligand for Aromatase Enzyme and HIV-1 Reverse Transcriptase Using Molegro Virtual Docker
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.