Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia
Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through...
Saved in:
| Published in | Journal of medicinal chemistry Vol. 61; no. 9; pp. 4155 - 4164 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Chemical Society
10.05.2018
American Chemical Society (ACS) |
| Subjects | |
| Online Access | Get full text |
Cover
Loading…
| Abstract | Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C424), which is not contained in PKM1. This interaction promotes more tetramer formation, inhibits the lysine433 (K433) acetylation, and influences the translocation of PKM2 into the nucleus. In addition, the pro-drug dimethylaminomicheliolide (DMAMCL) with similar properties as MCL significantly suppresses the growth of leukemia cells and tumorigenesis in a zebrafish xenograft model. Cell-based assay with knock down PKM2 expression verifies that the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia. Our discovery may provide a valuable pharmacological mechanism for clinical treatment and benefit the development of new anticancer agents. |
|---|---|
| AbstractList | Metabolic reprogramming
of cancer cells is essential for tumorigenesis
in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate
kinase, plays a critical role. Herein, we describe the identification
of a nature-product-derived micheliolide (MCL) that selectively activates
PKM2 through the covalent binding at residue cysteine424 (C424), which
is not contained in PKM1. This interaction promotes more tetramer
formation, inhibits the lysine433 (K433) acetylation, and influences
the translocation of PKM2 into the nucleus. In addition, the pro-drug
dimethylaminomicheliolide (DMAMCL) with similar properties as MCL
significantly suppresses the growth of leukemia cells and tumorigenesis
in a zebrafish xenograft model. Cell-based assay with knock down PKM2
expression verifies that the effects of MCL are dependent on PKM2
expression. DMAMCL is currently in clinical trials in Australia. Our
discovery may provide a valuable pharmacological mechanism for clinical
treatment and benefit the development of new anticancer agents. Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C424), which is not contained in PKM1. This interaction promotes more tetramer formation, inhibits the lysine433 (K433) acetylation, and influences the translocation of PKM2 into the nucleus. In addition, the pro-drug dimethylaminomicheliolide (DMAMCL) with similar properties as MCL significantly suppresses the growth of leukemia cells and tumorigenesis in a zebrafish xenograft model. Cell-based assay with knock down PKM2 expression verifies that the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia. Our discovery may provide a valuable pharmacological mechanism for clinical treatment and benefit the development of new anticancer agents. Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C424), which is not contained in PKM1. This interaction promotes more tetramer formation, inhibits the lysine433 (K433) acetylation, and influences the translocation of PKM2 into the nucleus. In addition, the pro-drug dimethylaminomicheliolide (DMAMCL) with similar properties as MCL significantly suppresses the growth of leukemia cells and tumorigenesis in a zebrafish xenograft model. Cell-based assay with knock down PKM2 expression verifies that the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia. Our discovery may provide a valuable pharmacological mechanism for clinical treatment and benefit the development of new anticancer agents.Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C424), which is not contained in PKM1. This interaction promotes more tetramer formation, inhibits the lysine433 (K433) acetylation, and influences the translocation of PKM2 into the nucleus. In addition, the pro-drug dimethylaminomicheliolide (DMAMCL) with similar properties as MCL significantly suppresses the growth of leukemia cells and tumorigenesis in a zebrafish xenograft model. Cell-based assay with knock down PKM2 expression verifies that the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia. Our discovery may provide a valuable pharmacological mechanism for clinical treatment and benefit the development of new anticancer agents. |
| Author | Zhao, Caili Ding, Yahui Liu, Ning Long, Haibo Guo, Jianshuang Ma, Cheng Luo, Ming Yan, Chunli Wen, Liuqing Li, Qiuying Ivanov, Ivaylo Li, Jing Xi, Rimo Li, Liangwei Li, Keqin Kathy Wu, Zhigang Chen, Yue Long, Jing Zhu, He Wang, Peng George Xue, Qingqing Zhang, Quan Li, Shanshan |
| AuthorAffiliation | Center for Diagnostics and Therapeutics, Department of Chemistry Department of Nephrology State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research Zhujiang Hospital, Southern Medical University |
| AuthorAffiliation_xml | – name: Department of Nephrology – name: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research – name: Center for Diagnostics and Therapeutics, Department of Chemistry – name: Zhujiang Hospital, Southern Medical University |
| Author_xml | – sequence: 1 givenname: Jing orcidid: 0000-0002-4289-4829 surname: Li fullname: Li, Jing organization: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research – sequence: 2 givenname: Shanshan surname: Li fullname: Li, Shanshan organization: Center for Diagnostics and Therapeutics, Department of Chemistry – sequence: 3 givenname: Jianshuang surname: Guo fullname: Guo, Jianshuang organization: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research – sequence: 4 givenname: Qiuying surname: Li fullname: Li, Qiuying organization: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research – sequence: 5 givenname: Jing surname: Long fullname: Long, Jing organization: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research – sequence: 6 givenname: Cheng orcidid: 0000-0002-0017-2182 surname: Ma fullname: Ma, Cheng organization: Center for Diagnostics and Therapeutics, Department of Chemistry – sequence: 7 givenname: Yahui surname: Ding fullname: Ding, Yahui organization: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research – sequence: 8 givenname: Chunli surname: Yan fullname: Yan, Chunli organization: Center for Diagnostics and Therapeutics, Department of Chemistry – sequence: 9 givenname: Liangwei surname: Li fullname: Li, Liangwei organization: Center for Diagnostics and Therapeutics, Department of Chemistry – sequence: 10 givenname: Zhigang surname: Wu fullname: Wu, Zhigang organization: Center for Diagnostics and Therapeutics, Department of Chemistry – sequence: 11 givenname: He surname: Zhu fullname: Zhu, He organization: Center for Diagnostics and Therapeutics, Department of Chemistry – sequence: 12 givenname: Keqin Kathy surname: Li fullname: Li, Keqin Kathy organization: Center for Diagnostics and Therapeutics, Department of Chemistry – sequence: 13 givenname: Liuqing surname: Wen fullname: Wen, Liuqing organization: Center for Diagnostics and Therapeutics, Department of Chemistry – sequence: 14 givenname: Quan surname: Zhang fullname: Zhang, Quan organization: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research – sequence: 15 givenname: Qingqing surname: Xue fullname: Xue, Qingqing organization: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research – sequence: 16 givenname: Caili surname: Zhao fullname: Zhao, Caili organization: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research – sequence: 17 givenname: Ning surname: Liu fullname: Liu, Ning organization: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research – sequence: 18 givenname: Ivaylo orcidid: 0000-0002-5306-1005 surname: Ivanov fullname: Ivanov, Ivaylo organization: Center for Diagnostics and Therapeutics, Department of Chemistry – sequence: 19 givenname: Ming orcidid: 0000-0003-1766-3487 surname: Luo fullname: Luo, Ming organization: Center for Diagnostics and Therapeutics, Department of Chemistry – sequence: 20 givenname: Rimo surname: Xi fullname: Xi, Rimo organization: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research – sequence: 21 givenname: Haibo surname: Long fullname: Long, Haibo organization: Zhujiang Hospital, Southern Medical University – sequence: 22 givenname: Peng George orcidid: 0000-0003-3335-6794 surname: Wang fullname: Wang, Peng George email: pwang11@gsu.edu organization: Center for Diagnostics and Therapeutics, Department of Chemistry – sequence: 23 givenname: Yue orcidid: 0000-0002-1317-7097 surname: Chen fullname: Chen, Yue email: yuechen@nankai.edu.cn organization: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29641204$$D View this record in MEDLINE/PubMed https://www.osti.gov/servlets/purl/1543635$$D View this record in Osti.gov |
| BookMark | eNqFkUFvEzEQhS1URNPCP0DI4lQOG2yvd9fmgFRFFCoSqAScLa93lrjs2sH2Rsq_r0PSCjjAyZbne88z887QifMOEHpOyZwSRl9rE-e3I3RmDeNctIQwTh-hGa0YKbgg_ATN8hsrWM3KU3QW4y0hpKSsfIJOmaw5ZYTPUPdJpynoAd8E300m4ZXNhoP1g-0AX6wWy1f4OgTYQoi2HXb40iS71QkivtmFaX_DH63TEfCKYe06_GXabALEmIklTD9gtPopetzrIcKz43mOvl29-7r4UCw_v79eXC4LzZs6FSDqhkJbih44ExJYSzoqdUfqVkrRQFeXOiMVlbyvRCs60_amJL2kjcwD9eU5envw3UztfjPgUh5NbYIdddgpr636s-LsWn33W1VJLhtGs8HLg4GPyapobAKzNt45MEnRipd1WWXo4vhL8D8niEmNNhoYBu3AT1GxnASvKyFYRl_83tBDJ_f7zwA_ACb4GAP0Dwglah-zyjGr-5jVMeYse_OXLLeqk_X7sezwPzE5iH9V_RRczuTfkjv1U8Mw |
| CitedBy_id | crossref_primary_10_3389_fonc_2021_767026 crossref_primary_10_3390_cancers14194568 crossref_primary_10_3389_fphar_2022_1035882 crossref_primary_10_1016_j_biopha_2024_116562 crossref_primary_10_1080_14728214_2020_1819982 crossref_primary_10_1002_cmdc_202400127 crossref_primary_10_1016_j_ejmech_2025_117242 crossref_primary_10_1007_s00109_019_01757_1 crossref_primary_10_1016_j_freeradbiomed_2022_05_007 crossref_primary_10_3389_fonc_2019_00993 crossref_primary_10_3390_ijms21093392 crossref_primary_10_3389_fimmu_2021_748573 crossref_primary_10_1016_j_bioorg_2021_104973 crossref_primary_10_1016_j_biomaterials_2023_122060 crossref_primary_10_1016_j_ejmech_2022_114254 crossref_primary_10_1038_s41419_019_1986_2 crossref_primary_10_3390_biomedicines10020514 crossref_primary_10_1016_j_ijbiomac_2021_10_213 crossref_primary_10_1186_s12967_023_04469_w crossref_primary_10_3892_ol_2019_10948 crossref_primary_10_1016_j_ejmech_2021_114070 crossref_primary_10_3389_fphar_2022_1036502 crossref_primary_10_1016_j_ejphar_2024_176529 crossref_primary_10_1007_s11030_022_10402_y crossref_primary_10_1021_acs_jmedchem_9b00763 crossref_primary_10_1089_ars_2022_0088 crossref_primary_10_1016_j_phrs_2019_104506 crossref_primary_10_1080_17460441_2023_2147920 crossref_primary_10_1021_acs_jafc_1c01651 crossref_primary_10_1042_BSR20192453 crossref_primary_10_1039_C9CS00720B crossref_primary_10_1021_acs_jmedchem_2c01563 crossref_primary_10_1186_s12935_021_02330_y crossref_primary_10_1038_s41401_024_01461_y crossref_primary_10_1007_s13258_023_01455_w crossref_primary_10_1021_acssensors_0c00897 crossref_primary_10_1039_D0RA07170F crossref_primary_10_1007_s00044_023_03181_0 crossref_primary_10_1021_acscentsci_0c01624 crossref_primary_10_1039_D1MD00045D crossref_primary_10_3390_molecules29020393 crossref_primary_10_1016_j_heliyon_2025_e42238 crossref_primary_10_1159_000504344 crossref_primary_10_1186_s13046_019_1107_1 crossref_primary_10_1016_j_tips_2021_03_008 crossref_primary_10_1155_2020_3934769 crossref_primary_10_2139_ssrn_3984021 crossref_primary_10_1111_jcmm_17007 crossref_primary_10_1016_j_biomaterials_2022_121523 crossref_primary_10_1016_j_jpbao_2024_100047 crossref_primary_10_3389_fimmu_2022_873054 crossref_primary_10_1038_s41401_021_00856_5 crossref_primary_10_1021_jacs_9b08001 crossref_primary_10_1007_s12032_024_02575_3 crossref_primary_10_1016_j_intimp_2022_109404 crossref_primary_10_1007_s00109_019_01839_0 crossref_primary_10_1055_a_2413_0587 crossref_primary_10_1016_S1875_5364_22_60238_3 crossref_primary_10_1021_acssynbio_2c00132 crossref_primary_10_1016_j_bbrc_2020_03_182 crossref_primary_10_1111_1759_7714_14453 crossref_primary_10_1007_s12265_022_10321_1 crossref_primary_10_1111_cpr_13700 crossref_primary_10_1186_s12964_024_01478_0 crossref_primary_10_1016_j_bmcl_2021_128062 crossref_primary_10_1021_acs_jmedchem_0c01449 crossref_primary_10_1097_BS9_0000000000000168 crossref_primary_10_1021_acs_chemrestox_4c00154 crossref_primary_10_1186_s12885_024_12792_8 crossref_primary_10_1002_adtp_202100100 crossref_primary_10_1021_acs_jmedchem_4c02334 crossref_primary_10_1002_ptr_7534 crossref_primary_10_1016_j_bioorg_2021_104653 crossref_primary_10_1021_acs_jnatprod_1c00936 crossref_primary_10_1016_j_ejmech_2020_112896 crossref_primary_10_1016_j_intimp_2022_109431 crossref_primary_10_1016_j_bioorg_2020_104518 crossref_primary_10_1155_2022_3744837 crossref_primary_10_1016_j_cmet_2022_07_014 crossref_primary_10_1038_s41598_023_38448_4 crossref_primary_10_1021_acschembio_4c00624 crossref_primary_10_18632_aging_101932 crossref_primary_10_1016_j_bbr_2019_112337 crossref_primary_10_1016_j_molstruc_2024_137751 crossref_primary_10_2174_0929867331666230714144851 crossref_primary_10_3390_cancers16142533 crossref_primary_10_1016_j_ejps_2021_106112 crossref_primary_10_1186_s12964_023_01282_2 crossref_primary_10_1016_j_bcp_2025_116759 crossref_primary_10_1039_D3OB01019H crossref_primary_10_1021_acs_jmedchem_1c00981 crossref_primary_10_1093_carcin_bgz180 crossref_primary_10_1016_j_heliyon_2023_e17848 crossref_primary_10_1042_BCJ20200897 crossref_primary_10_1016_j_canlet_2020_04_003 crossref_primary_10_1038_s41389_023_00462_6 crossref_primary_10_1007_s00432_022_04542_9 crossref_primary_10_3389_fimmu_2023_1188760 crossref_primary_10_1002_adtp_202100160 crossref_primary_10_1038_s41419_021_03782_w crossref_primary_10_1021_acs_orglett_2c01215 crossref_primary_10_1021_acs_orglett_1c03120 crossref_primary_10_3390_ph18030287 crossref_primary_10_1016_j_ejmech_2019_03_003 crossref_primary_10_1186_s12964_022_00862_y crossref_primary_10_3390_cancers16203513 crossref_primary_10_3389_fphar_2025_1551115 crossref_primary_10_1111_1759_7714_70028 |
| Cites_doi | 10.1016/j.molcel.2013.09.004 10.1158/1535-7163.MCT-13-0026 10.1016/j.cell.2011.03.054 10.1016/j.chembiol.2009.02.013 10.1038/nrc723 10.15252/embr.201643300 10.1084/jem.20111487 10.1371/journal.pone.0116202 10.1016/j.chembiol.2014.08.007 10.1182/blood-2004-10-4135 10.1038/ncb3630 10.1006/jmbi.1996.0897 10.1073/pnas.1212780110 10.1038/nature10598 10.1208/pt0804105 10.1021/jm301064b 10.1073/pnas.1704145115 10.1016/j.cell.2014.07.048 10.1016/j.cell.2012.07.018 10.1038/nchembio.1060 10.1016/j.molcel.2012.01.001 10.1182/blood.V122.21.3892.3892 10.1002/jps.2600620244 10.1038/nature11540 10.1038/nature06734 10.1126/science.1211485 10.1038/nature06667 10.3324/haematol.2009.011437 10.1186/s12943-015-0490-2 10.1038/ncomms6566 10.1126/science.1224409 10.1016/j.cell.2013.09.025 |
| ContentType | Journal Article |
| Copyright | Copyright © 2018 American Chemical Society 2018 American Chemical Society |
| Copyright_xml | – notice: Copyright © 2018 American Chemical Society 2018 American Chemical Society |
| CorporateAuthor | Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC) Univ. of California, Oakland, CA (United States) |
| CorporateAuthor_xml | – name: Univ. of California, Oakland, CA (United States) – name: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC) |
| DBID | AAYXX CITATION CGR CUY CVF ECM EIF NPM 7X8 OIOZB OTOTI 5PM |
| DOI | 10.1021/acs.jmedchem.8b00241 |
| DatabaseName | CrossRef Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic OSTI.GOV - Hybrid OSTI.GOV PubMed Central (Full Participant titles) |
| DatabaseTitle | CrossRef MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic |
| DatabaseTitleList | MEDLINE MEDLINE - Academic |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: EIF name: MEDLINE url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/medline/basic-search sourceTypes: Index Database |
| DeliveryMethod | fulltext_linktorsrc |
| Discipline | Chemistry Pharmacy, Therapeutics, & Pharmacology |
| EISSN | 1520-4804 |
| EndPage | 4164 |
| ExternalDocumentID | PMC5949721 1543635 29641204 10_1021_acs_jmedchem_8b00241 c530356100 |
| Genre | Research Support, U.S. Gov't, Non-P.H.S Research Support, Non-U.S. Gov't Journal Article |
| GrantInformation_xml | – fundername: NIGMS NIH HHS grantid: R01 GM110387 – fundername: NIGMS NIH HHS grantid: U01 GM116263 |
| GroupedDBID | - .K2 55A 5GY 5RE 5VS 7~N AABXI ABFLS ABMVS ABOCM ABPTK ABUCX ACGFS ACJ ACS AEESW AENEX AFEFF ALMA_UNASSIGNED_HOLDINGS AQSVZ BAANH CS3 DU5 EBS ED ED~ EJD F5P GNL IH9 IHE JG JG~ K2 L7B LG6 P2P ROL TN5 UI2 VF5 VG9 W1F WH7 X XFK YZZ ZY4 --- -~X 4.4 6P2 AAHBH AAYXX ABBLG ABJNI ABLBI ABQRX ACGFO ADHLV AGXLV AHGAQ CITATION CUPRZ GGK IH2 XSW YQT CGR CUY CVF ECM EIF NPM 7X8 ABTAH OIOZB OTOTI 5PM |
| ID | FETCH-LOGICAL-a476t-e8671eb38fe4289e2b0d19ad06b9987ed63a8675194f58b8dcbfc30f9179964f3 |
| IEDL.DBID | ACS |
| ISSN | 0022-2623 1520-4804 |
| IngestDate | Thu Aug 21 13:55:16 EDT 2025 Mon Nov 25 02:38:32 EST 2024 Fri Jul 11 01:10:41 EDT 2025 Mon Jul 21 05:52:06 EDT 2025 Thu Apr 24 23:11:28 EDT 2025 Tue Jul 01 00:42:55 EDT 2025 Thu Aug 27 13:42:35 EDT 2020 |
| IsDoiOpenAccess | true |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 9 |
| Language | English |
| License | http://pubs.acs.org/page/policy/authorchoice_termsofuse.html This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-a476t-e8671eb38fe4289e2b0d19ad06b9987ed63a8675194f58b8dcbfc30f9179964f3 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AC02-05CH11231 USDOE Office of Science (SC) |
| ORCID | 0000-0002-0017-2182 0000-0002-4289-4829 0000-0003-1766-3487 0000-0003-3335-6794 0000-0002-1317-7097 0000-0002-5306-1005 0000000253061005 0000000213177097 0000000200172182 0000000242894829 0000000333356794 |
| OpenAccessLink | https://www.osti.gov/servlets/purl/1543635 |
| PMID | 29641204 |
| PQID | 2024465882 |
| PQPubID | 23479 |
| PageCount | 10 |
| ParticipantIDs | pubmedcentral_primary_oai_pubmedcentral_nih_gov_5949721 osti_scitechconnect_1543635 proquest_miscellaneous_2024465882 pubmed_primary_29641204 crossref_primary_10_1021_acs_jmedchem_8b00241 crossref_citationtrail_10_1021_acs_jmedchem_8b00241 acs_journals_10_1021_acs_jmedchem_8b00241 |
| ProviderPackageCode | JG~ 55A AABXI GNL VF5 7~N ACJ VG9 W1F ACS AEESW AFEFF .K2 ABMVS ABUCX IH9 BAANH AQSVZ ED~ UI2 CITATION AAYXX |
| PublicationCentury | 2000 |
| PublicationDate | 2018-05-10 |
| PublicationDateYYYYMMDD | 2018-05-10 |
| PublicationDate_xml | – month: 05 year: 2018 text: 2018-05-10 day: 10 |
| PublicationDecade | 2010 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States |
| PublicationTitle | Journal of medicinal chemistry |
| PublicationTitleAlternate | J. Med. Chem |
| PublicationYear | 2018 |
| Publisher | American Chemical Society American Chemical Society (ACS) |
| Publisher_xml | – name: American Chemical Society – name: American Chemical Society (ACS) |
| References | ref9/cit9 ref6/cit6 ref3/cit3 ref27/cit27 ref18/cit18 ref11/cit11 ref25/cit25 ref16/cit16 ref29/cit29 ref32/cit32 ref23/cit23 ref14/cit14 ref8/cit8 ref5/cit5 ref31/cit31 ref2/cit2 ref28/cit28 ref20/cit20 ref17/cit17 ref10/cit10 ref26/cit26 Guzman M. L. (ref24/cit24) 2013; 122 ref19/cit19 ref21/cit21 ref12/cit12 ref15/cit15 ref22/cit22 ref13/cit13 ref4/cit4 ref30/cit30 ref1/cit1 ref7/cit7 |
| References_xml | – ident: ref20/cit20 doi: 10.1016/j.molcel.2013.09.004 – ident: ref32/cit32 doi: 10.1158/1535-7163.MCT-13-0026 – ident: ref31/cit31 doi: 10.1016/j.cell.2011.03.054 – ident: ref18/cit18 doi: 10.1016/j.chembiol.2009.02.013 – ident: ref11/cit11 doi: 10.1038/nrc723 – ident: ref3/cit3 doi: 10.15252/embr.201643300 – ident: ref23/cit23 doi: 10.1084/jem.20111487 – ident: ref15/cit15 doi: 10.1371/journal.pone.0116202 – ident: ref10/cit10 doi: 10.1016/j.chembiol.2014.08.007 – ident: ref12/cit12 doi: 10.1182/blood-2004-10-4135 – ident: ref29/cit29 doi: 10.1038/ncb3630 – ident: ref22/cit22 doi: 10.1006/jmbi.1996.0897 – ident: ref27/cit27 doi: 10.1073/pnas.1212780110 – ident: ref21/cit21 doi: 10.1038/nature10598 – ident: ref14/cit14 doi: 10.1208/pt0804105 – ident: ref16/cit16 doi: 10.1021/jm301064b – ident: ref28/cit28 doi: 10.1073/pnas.1704145115 – ident: ref26/cit26 doi: 10.1016/j.cell.2014.07.048 – ident: ref8/cit8 doi: 10.1016/j.cell.2012.07.018 – ident: ref9/cit9 doi: 10.1038/nchembio.1060 – ident: ref7/cit7 doi: 10.1016/j.molcel.2012.01.001 – volume: 122 start-page: 5406 year: 2013 ident: ref24/cit24 publication-title: Blood doi: 10.1182/blood.V122.21.3892.3892 – ident: ref13/cit13 doi: 10.1002/jps.2600620244 – ident: ref2/cit2 doi: 10.1038/nature11540 – ident: ref1/cit1 doi: 10.1038/nature06734 – ident: ref17/cit17 doi: 10.1126/science.1211485 – ident: ref19/cit19 doi: 10.1038/nature06667 – ident: ref25/cit25 doi: 10.3324/haematol.2009.011437 – ident: ref6/cit6 doi: 10.1186/s12943-015-0490-2 – ident: ref30/cit30 doi: 10.1038/ncomms6566 – ident: ref4/cit4 doi: 10.1126/science.1224409 – ident: ref5/cit5 doi: 10.1016/j.cell.2013.09.025 |
| SSID | ssj0003123 |
| Score | 2.5787897 |
| Snippet | Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a... Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a... |
| SourceID | pubmedcentral osti proquest pubmed crossref acs |
| SourceType | Open Access Repository Aggregation Database Index Database Enrichment Source Publisher |
| StartPage | 4155 |
| SubjectTerms | 60 APPLIED LIFE SCIENCES Acetylation - drug effects Active Transport, Cell Nucleus - drug effects Amino Acid Sequence Animals Antineoplastic Agents - pharmacology Carcinogenesis - drug effects Carrier Proteins - chemistry Carrier Proteins - metabolism Cell Line, Tumor Cell Nucleus - drug effects Cell Nucleus - metabolism Enzyme Activation - drug effects Gene Expression Regulation, Neoplastic - drug effects Humans Leukemia - pathology Membrane Proteins - chemistry Membrane Proteins - metabolism Pharmacology & Pharmacy Phosphorylation - drug effects Protein Domains Protein Multimerization Protein Structure, Quaternary Sesquiterpenes, Guaiane - pharmacology Substrate Specificity Thyroid Hormone-Binding Proteins Thyroid Hormones - chemistry Thyroid Hormones - metabolism Xenograft Model Antitumor Assays Zebrafish |
| Title | Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia |
| URI | http://dx.doi.org/10.1021/acs.jmedchem.8b00241 https://www.ncbi.nlm.nih.gov/pubmed/29641204 https://www.proquest.com/docview/2024465882 https://www.osti.gov/servlets/purl/1543635 https://pubmed.ncbi.nlm.nih.gov/PMC5949721 |
| Volume | 61 |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwlZ3fb9MwEMctVB7ghcH4FQaTkdDEpKU4zg87j1O1acA6KrFJe4v8U-tWUtQkD-Wv5-wkLR2gwVvV2m3q3OW-J58_h9A7S40lNuIhscxCgkJkKJPMhDy1qWZGmJy4w8njs-zkIvl0mV6uE8XbO_g0-iBUNbx2xYpX5tuQ-6AC2c59moEfOyk0-rp68sYRjXs6OIW43h-V-8u3uICkqo2ANJiDY_1JbN6umfwlCB1voS_9UZ629uRm2NRyqH78Tnb8x__3GD3q9Cg-bA3oCbpnym30YNS3gdtGe5MWbr08wOfrs1rVAd7DkzX2evkU6TPhGR540kJkcVtlOp3Pptrg9-PR6T7-uHDEqAW44WyJD5VvrWYqPFkuGvcKf56WEFXxmGJRauw6jnq2eYVPTXMDlySeoYvjo_PRSdj1cAhFwrI6NI6fBwk7twYSndxQSXSUC00yCYkeMzqLBQwBHZnYlEuulbQqJjZ3pLossfFzNCjnpXmJsIHnhyKa5SqViWSaZxDfGbcxya1mqQnQPqxl0flgVfjtdRoV_s1ugYtugQMU9ze9UB0M3fXkmN0xK1zN-t7CQO4Yv-PsqQAx44i8ypUuqboA1RqDzgvQ297MCrinbqNGlGbeVAWFyQlIQ04D9KI1u9XvuW3yiJIkQGzDIFcDHC9885NyeuW54WmeOFbTq_9Ypx30EBQiDz2u9jUa1IvGvAEVVstd73o_AVbSMUI |
| linkProvider | American Chemical Society |
| linkToHtml | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwlZ3ba9swFIdFyR66l126m9tdNBhlhTqT5Zv8GMJKuiYhsHT0zVg3mjV1Rmw_ZH_9juRLlrJR-hYcyRf5yOd30NF3EPqkqdJEe8wlOtYQoBDu8iBSLgt1KGOVqYSYzcmTaTS6DL5dhVd7KGz3wsBNFHCmwi7ib-kC3hdz7KfJWbxWt31mfQsEPY9Aj1Bj2IPh9-4D7HvUbyHhFNx7u2PuP2cxfkkUO36pt4L59S_NeTd18i9fdPYU_eiewqag3PSrkvfF7zuAxwc_5jP0pFGneFCb03O0p_IDtD9si8IdoONZjbrenOL5dudWcYqP8WwLwd68QHKaWaIHntVIWVznnC5Wy4VU-PNkOD7B52vDj1rDpFxu8EDYQmuqwLPNujK_8MUiBx-LJxRnucSm_qglnRd4rKobuKXsJbo8-zofjtymooObBXFUusrQ9CB8Z1pB2JMoyon0kkySiEPYFysZ-Rk0AVUZ6JBxJgXXwic6Mdy6KND-K9TLV7l6g7CCr4kgMk5EyAMeSxaBt4-Z9kmiZRwqB53AWKbNjCxSu9hOvdQebAY4bQbYQX777lPRoNFNhY7lPb3crtevGg1yT_sjY1YpSBvD5xUmkUmUKWhYH1Sfgz621pbCOzXLNlmuVlWRUugcgFBk1EGva-vrrmcWzT1KAgfFO3bZNTD08N1_8sW1pYiHSWDITYcPGKcPaH80n4zT8fn04gg9Bu3IXAuyfYt65bpS70Cflfy9nY1_AHlLOaM |
| linkToPdf | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnZ1Za9tAEICX4kLblx7ppabHFkpoIHJX9-rRuDVJYxtBEwh9WbQXcePKwZIe3F_f2dWROLSE9s3IuzpWM5oZZvYbhD5oX2miPeoSnWgIUAh3eRgrl0Y6konKVUrM5uTZPD48Db-eRWfXWn3BTZRwptIm8Y1WX0rdEga8T-b4D1O3eK5-Dqm1LxD43DWZOyPco_G3_iMceH7QgcJ9MPHdrrm_nMXYJlFu2abBCnTsT37nzfLJa_Zo8gh975_ElqFcDOuKD8WvG5DH_3rUx-hh66XiUSNWT9AdVeyg--OuOdwO2ssa5PXmAJ9c7eAqD_Aezq5g2JunSM5zS_bAWYOWxU3t6WK1XEiFP87G0318tDYcqTUo53KDR8I2XFMlzjbr2vzCx4sCbC2e-TgvJDZ9SC3xvMRTVV_ALeXP0Onky8n40G07O7h5mMSVqwxVD8J4qhWEP6nyOZFemksScwj_EiXjIIch4F2GOqKcSsG1CIhODb8uDnXwHA2KVaFeIqzgqyKITFIR8ZAnksZg9ROqA5JqmUTKQfuwlqzVzJLZpLvvMXuwXWDWLrCDgu79M9Ei0k2njuUts9x-1mWDCLll_K4RLQYujuH0ClPQJCoGvmwA3p-D3ncSx-CdmvRNXqhVXTIfJofgMFLfQS8aCeyvZ5Lnnk9CByVbstkPMBTx7X-KxbmliUdpaAhOr_5hnd6he9nnCZsezY930QNwIalrebav0aBa1-oNuGkVf2sV8jdYHDwm |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Natural+Product+Micheliolide+%28MCL%29+Irreversibly+Activates+Pyruvate+Kinase+M2+and+Suppresses+Leukemia&rft.jtitle=Journal+of+medicinal+chemistry&rft.au=Li%2C+Jing&rft.au=Li%2C+Shanshan&rft.au=Guo%2C+Jianshuang&rft.au=Li%2C+Qiuying&rft.date=2018-05-10&rft.pub=American+Chemical+Society+%28ACS%29&rft.issn=0022-2623&rft.volume=61&rft.issue=9&rft_id=info:doi/10.1021%2Facs.jmedchem.8b00241&rft.externalDocID=1543635 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0022-2623&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0022-2623&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0022-2623&client=summon |