Gast ::
| Hauptseite > Publikationsdatenbank > Targeting HSP90 dimerization via the C-terminus is effective in imatinib resistant CML and lacks heat shock response > print |
| Hauptseite > Publikationsdatenbank > Targeting HSP90 dimerization via the C-terminus is effective in imatinib resistant CML and lacks heat shock response > print |
| 001 | 845779 | ||
| 005 | 20210129233641.0 | ||
| 024 | 7 | _ | |a 10.1182/blood-2017-10-810986 |2 doi |
| 024 | 7 | _ | |a 0006-4971 |2 ISSN |
| 024 | 7 | _ | |a 1528-0020 |2 ISSN |
| 024 | 7 | _ | |a pmid:29724897 |2 pmid |
| 024 | 7 | _ | |a WOS:000439131800011 |2 WOS |
| 024 | 7 | _ | |a altmetric:40684070 |2 altmetric |
| 037 | _ | _ | |a FZJ-2018-02988 |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Bhatia, Sanil |0 P:(DE-HGF)0 |b 0 |
| 245 | _ | _ | |a Targeting HSP90 dimerization via the C-terminus is effective in imatinib resistant CML and lacks heat shock response |
| 260 | _ | _ | |a Stanford, Calif. |c 2018 |b HighWire Press |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1533187184_29710 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a Heat shock protein 90 (HSP90) stabilizes many client proteins including BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of CML in which treatment-free remission (TFR) is limited with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics, which synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain (NTD) of HSP90 are under investigation; however, side effects such as induction of heat shock response (HSR) and toxicity have so far precluded their FDA approval. We have developed a novel inhibitor (referred to as aminoxyrone) of HSP90 function by targeting HSP90 dimerization via the C-terminal domain (CTD). This was achieved by structure-based molecular design, chemical synthesis, and functional pre-clinical in vitro and in vivo validation using CML cell lines and patient-derived CML cells. Aminoxyrone (AX) is a promising potential candidate, which induces apoptosis in leukemic stem cells (LSCs) fraction (CD34+CD38-) as well as the leukemic bulk (CD34+CD38+) of primary CML and in TKI-resistant cells. Furthermore, BCR-ABL1 oncoprotein and related pro-oncogenic cellular responses are downregulated and targeting HSP90 C-terminus by AX does not induce HSR in vitro and in vivo. We also probed the potential of AX in other therapy refractory leukemia such as BCR-ABL1+ BCP-ALL, FLT3-ITD+ AML and Ph-like BCP-ALL. Therefore, AX is the first peptidometic C-terminal HSP90 inhibitor with the potential to increase TFR in TKI sensitive and refractory CML patients and also offers a novel therapeutic option for patients with other therapy-refractory leukemia, due to its low toxicity profile and lack of HSR. |
| 536 | _ | _ | |a 511 - Computational Science and Mathematical Methods (POF3-511) |0 G:(DE-HGF)POF3-511 |c POF3-511 |f POF III |x 0 |
| 536 | _ | _ | |a 561 - Biological Key Regulators and Small Chemical Compounds (POF3-561) |0 G:(DE-HGF)POF3-561 |c POF3-561 |f POF III |x 1 |
| 536 | _ | _ | |a 316 - Infections and cancer (POF3-316) |0 G:(DE-HGF)POF3-316 |c POF3-316 |f POF III |x 2 |
| 536 | _ | _ | |a Forschergruppe Gohlke (hkf7_20170501) |0 G:(DE-Juel1)hkf7_20170501 |c hkf7_20170501 |f Forschergruppe Gohlke |x 3 |
| 588 | _ | _ | |a Dataset connected to CrossRef |
| 700 | 1 | _ | |a Diedrich, Daniela |0 P:(DE-HGF)0 |b 1 |
| 700 | 1 | _ | |a Frieg, Benedikt |0 P:(DE-Juel1)172887 |b 2 |u fzj |
| 700 | 1 | _ | |a Ahlert, Heinz |0 P:(DE-HGF)0 |b 3 |
| 700 | 1 | _ | |a Stein, Stefan |0 P:(DE-HGF)0 |b 4 |
| 700 | 1 | _ | |a Bopp, Bertan |0 P:(DE-HGF)0 |b 5 |
| 700 | 1 | _ | |a Lang, Franziska |0 P:(DE-HGF)0 |b 6 |
| 700 | 1 | _ | |a Zang, Tao |0 P:(DE-HGF)0 |b 7 |
| 700 | 1 | _ | |a Kröger, Tobias |0 P:(DE-HGF)0 |b 8 |
| 700 | 1 | _ | |a Ernst, Thomas |0 P:(DE-HGF)0 |b 9 |
| 700 | 1 | _ | |a Kögler, Gesine |0 P:(DE-HGF)0 |b 10 |
| 700 | 1 | _ | |a Krieg, Andreas |0 P:(DE-HGF)0 |b 11 |
| 700 | 1 | _ | |a Lüdeke, Steffen |0 P:(DE-HGF)0 |b 12 |
| 700 | 1 | _ | |a Kunkel, Hana |0 P:(DE-HGF)0 |b 13 |
| 700 | 1 | _ | |a Rodrigues Moita, Ana J. |0 P:(DE-HGF)0 |b 14 |
| 700 | 1 | _ | |a Kassack, Matthias U. |0 P:(DE-HGF)0 |b 15 |
| 700 | 1 | _ | |a Marquardt, Viktoria |0 P:(DE-HGF)0 |b 16 |
| 700 | 1 | _ | |a Opitz, Friederike V. |0 P:(DE-HGF)0 |b 17 |
| 700 | 1 | _ | |a Oldenburg, Marina |0 P:(DE-HGF)0 |b 18 |
| 700 | 1 | _ | |a Remke, Marc |0 P:(DE-HGF)0 |b 19 |
| 700 | 1 | _ | |a Babor, Florian |0 P:(DE-HGF)0 |b 20 |
| 700 | 1 | _ | |a Grez, Manuel |0 P:(DE-HGF)0 |b 21 |
| 700 | 1 | _ | |a Hochhaus, Andreas |0 P:(DE-HGF)0 |b 22 |
| 700 | 1 | _ | |a Borkhardt, Arndt |0 P:(DE-HGF)0 |b 23 |
| 700 | 1 | _ | |a Groth, Georg |0 P:(DE-HGF)0 |b 24 |
| 700 | 1 | _ | |a Nagel-Steger, Luitgard |0 P:(DE-Juel1)162443 |b 25 |u fzj |
| 700 | 1 | _ | |a Jose, Joachim |0 P:(DE-HGF)0 |b 26 |
| 700 | 1 | _ | |a Kurz, Thomas |0 P:(DE-HGF)0 |b 27 |
| 700 | 1 | _ | |a Gohlke, Holger |0 P:(DE-Juel1)172663 |b 28 |u fzj |
| 700 | 1 | _ | |a Hansen, Finn K. |0 P:(DE-HGF)0 |b 29 |e Corresponding author |
| 700 | 1 | _ | |a Hauer, Julia |0 P:(DE-HGF)0 |b 30 |e Corresponding author |
| 773 | _ | _ | |a 10.1182/blood-2017-10-810986 |g p. blood-2017-10-810986 - |0 PERI:(DE-600)1468538-3 |n 3 |p 307-320 |t Blood |v 132 |y 2018 |x 1528-0020 |
| 909 | C | O | |o oai:juser.fz-juelich.de:845779 |p VDB |
| 910 | 1 | _ | |a Forschungszentrum Jülich |0 I:(DE-588b)5008462-8 |k FZJ |b 2 |6 P:(DE-Juel1)172887 |
| 910 | 1 | _ | |a Forschungszentrum Jülich |0 I:(DE-588b)5008462-8 |k FZJ |b 25 |6 P:(DE-Juel1)162443 |
| 910 | 1 | _ | |a Forschungszentrum Jülich |0 I:(DE-588b)5008462-8 |k FZJ |b 28 |6 P:(DE-Juel1)172663 |
| 913 | 1 | _ | |a DE-HGF |b Key Technologies |1 G:(DE-HGF)POF3-510 |0 G:(DE-HGF)POF3-511 |2 G:(DE-HGF)POF3-500 |v Computational Science and Mathematical Methods |x 0 |4 G:(DE-HGF)POF |3 G:(DE-HGF)POF3 |l Supercomputing & Big Data |
| 913 | 1 | _ | |a DE-HGF |b Key Technologies |l BioInterfaces in Technology and Medicine |1 G:(DE-HGF)POF3-560 |0 G:(DE-HGF)POF3-561 |2 G:(DE-HGF)POF3-500 |v Biological Key Regulators and Small Chemical Compounds |x 1 |4 G:(DE-HGF)POF |3 G:(DE-HGF)POF3 |
| 913 | 1 | _ | |a DE-HGF |l Krebsforschung |1 G:(DE-HGF)POF3-310 |0 G:(DE-HGF)POF3-316 |2 G:(DE-HGF)POF3-300 |v Infections and cancer |x 2 |4 G:(DE-HGF)POF |3 G:(DE-HGF)POF3 |b Gesundheit |
| 914 | 1 | _ | |y 2018 |
| 915 | _ | _ | |a JCR |0 StatID:(DE-HGF)0100 |2 StatID |b BLOOD : 2015 |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)0200 |2 StatID |b SCOPUS |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)0300 |2 StatID |b Medline |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)0310 |2 StatID |b NCBI Molecular Biology Database |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)0600 |2 StatID |b Ebsco Academic Search |
| 915 | _ | _ | |a Peer Review |0 StatID:(DE-HGF)0030 |2 StatID |b ASC |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)0199 |2 StatID |b Thomson Reuters Master Journal List |
| 915 | _ | _ | |a WoS |0 StatID:(DE-HGF)0110 |2 StatID |b Science Citation Index |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)0150 |2 StatID |b Web of Science Core Collection |
| 915 | _ | _ | |a WoS |0 StatID:(DE-HGF)0111 |2 StatID |b Science Citation Index Expanded |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)1110 |2 StatID |b Current Contents - Clinical Medicine |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)1030 |2 StatID |b Current Contents - Life Sciences |
| 915 | _ | _ | |a DBCoverage |0 StatID:(DE-HGF)1050 |2 StatID |b BIOSIS Previews |
| 915 | _ | _ | |a IF >= 10 |0 StatID:(DE-HGF)9910 |2 StatID |b BLOOD : 2015 |
| 920 | _ | _ | |l yes |
| 920 | 1 | _ | |0 I:(DE-Juel1)JSC-20090406 |k JSC |l Jülich Supercomputing Center |x 0 |
| 920 | 1 | _ | |0 I:(DE-Juel1)NIC-20090406 |k NIC |l John von Neumann - Institut für Computing |x 1 |
| 920 | 1 | _ | |0 I:(DE-Juel1)ICS-6-20110106 |k ICS-6 |l Strukturbiochemie |x 2 |
| 980 | _ | _ | |a journal |
| 980 | _ | _ | |a VDB |
| 980 | _ | _ | |a I:(DE-Juel1)JSC-20090406 |
| 980 | _ | _ | |a I:(DE-Juel1)NIC-20090406 |
| 980 | _ | _ | |a I:(DE-Juel1)ICS-6-20110106 |
| 980 | _ | _ | |a UNRESTRICTED |
| 981 | _ | _ | |a I:(DE-Juel1)IBI-7-20200312 |
| Library | Collection | CLSMajor | CLSMinor | Language | Author |
|---|