PMID- 33289299 OWN - NLM STAT- MEDLINE DCOM- 20211213 LR - 20221005 IS - 2211-5463 (Electronic) IS - 2211-5463 (Linking) VI - 11 IP - 1 DP - 2021 Jan TI - Modulators of histone demethylase JMJD1C selectively target leukemic stem cells. PG - 265-277 LID - 10.1002/2211-5463.13054 [doi] AB - 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 the growth of LSCs. CI - (c) 2020 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. FAU - Yang, Yong AU - Yang Y AD - Laboratory for Stem Cell and Regenerative Medicine & Clinical Research Center, The Affiliated Hospital of Weifang Medical University, China. FAU - Zhang, Xinjing AU - Zhang X AD - Department of Anesthesiology, Zibo Central Hospital, China. FAU - Zhang, Xiaoyan AU - Zhang X AD - The Department of Obstetrics and Gynecology, The Affiliated Hospital of Weifang Medical University, China. FAU - Wang, Yishu AU - Wang Y AD - Laboratory for Stem Cell and Regenerative Medicine & Clinical Research Center, The Affiliated Hospital of Weifang Medical University, China. FAU - Wang, Xintong AU - Wang X AD - Beijing Beike Deyuan Bio-Pharm Technology Co. Ltd, China. FAU - Hu, Linda AU - Hu L AD - Upstate Medical University, Syracuse, NY, USA. FAU - Zhao, Yao AU - Zhao Y AD - Laboratory for Stem Cell and Regenerative Medicine & Clinical Research Center, The Affiliated Hospital of Weifang Medical University, China. FAU - Wang, Haihua AU - Wang H AD - Laboratory for Stem Cell and Regenerative Medicine & Clinical Research Center, The Affiliated Hospital of Weifang Medical University, China. FAU - Wang, Zhanju AU - Wang Z AD - The Department of Hematology, the Affiliated Hospital of Weifang Medical University, China. FAU - Wang, Haiying AU - Wang H AD - The Department of Hematology, the Affiliated Hospital of Weifang Medical University, China. FAU - Wang, Lin AU - Wang L AD - The School of Physics and Optoelectronic Engineering, Weifang University, China. FAU - Dirks, Wilhelm G AU - Dirks WG AD - Department of Human and Animal Cell Culture, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany. FAU - Drexler, Hans G AU - Drexler HG AD - Department of Human and Animal Cell Culture, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany. FAU - Xu, Xin AU - Xu X AUID- ORCID: 0000-0002-8288-9047 AD - Laboratory for Stem Cell and Regenerative Medicine & Clinical Research Center, The Affiliated Hospital of Weifang Medical University, China. AD - School of Life Science and Technology, Weifang Medical University, China. FAU - Hu, Zhenbo AU - Hu Z AUID- ORCID: 0000-0002-6523-7397 AD - Laboratory for Stem Cell and Regenerative Medicine & Clinical Research Center, The Affiliated Hospital of Weifang Medical University, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201216 PL - England TA - FEBS Open Bio JT - FEBS open bio JID - 101580716 RN - 0 (Antineoplastic Agents) RN - 0 (Homeodomain Proteins) RN - 0 (homeobox protein HOXA9) RN - 742SXX0ICT (Tadalafil) RN - EC 1.14.11.- (JMJD1C protein, human) RN - EC 1.14.11.- (Jumonji Domain-Containing Histone Demethylases) RN - EC 1.5.- (Oxidoreductases, N-Demethylating) SB - IM MH - Antineoplastic Agents/*pharmacology/therapeutic use MH - Drug Screening Assays, Antitumor MH - Gene Expression Regulation, Leukemic/drug effects MH - Homeodomain Proteins/genetics MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Jumonji Domain-Containing Histone Demethylases/*antagonists & inhibitors MH - Leukemia, Myeloid, Acute/*drug therapy/genetics/pathology MH - Neoplastic Stem Cells/*drug effects/pathology MH - Oxidoreductases, N-Demethylating/*antagonists & inhibitors MH - Primary Cell Culture MH - Tadalafil/pharmacology/therapeutic use PMC - PMC7780120 OTO - NOTNLM OT - JMJD1B OT - JMJD1C OT - histone demethylases OT - leukemic stem cells OT - small molecular compounds COIS- The authors declare no conflict of interest. EDAT- 2020/12/09 06:00 MHDA- 2021/12/15 06:00 PMCR- 2020/12/16 CRDT- 2020/12/08 05:49 PHST- 2020/08/04 00:00 [received] PHST- 2020/11/19 00:00 [revised] PHST- 2020/11/30 00:00 [accepted] PHST- 2020/12/09 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2020/12/08 05:49 [entrez] PHST- 2020/12/16 00:00 [pmc-release] AID - FEB413054 [pii] AID - 10.1002/2211-5463.13054 [doi] PST - ppublish SO - FEBS Open Bio. 2021 Jan;11(1):265-277. doi: 10.1002/2211-5463.13054. Epub 2020 Dec 16.