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000845779 1001_ $$0P:(DE-HGF)0$$aBhatia, Sanil$$b0
000845779 245__ $$aTargeting HSP90 dimerization via the C-terminus is effective in imatinib resistant CML and lacks heat shock response
000845779 260__ $$aStanford, Calif.$$bHighWire Press$$c2018
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000845779 520__ $$aHeat 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.
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000845779 7001_ $$0P:(DE-HGF)0$$aDiedrich, Daniela$$b1
000845779 7001_ $$0P:(DE-Juel1)172887$$aFrieg, Benedikt$$b2$$ufzj
000845779 7001_ $$0P:(DE-HGF)0$$aAhlert, Heinz$$b3
000845779 7001_ $$0P:(DE-HGF)0$$aStein, Stefan$$b4
000845779 7001_ $$0P:(DE-HGF)0$$aBopp, Bertan$$b5
000845779 7001_ $$0P:(DE-HGF)0$$aLang, Franziska$$b6
000845779 7001_ $$0P:(DE-HGF)0$$aZang, Tao$$b7
000845779 7001_ $$0P:(DE-HGF)0$$aKröger, Tobias$$b8
000845779 7001_ $$0P:(DE-HGF)0$$aErnst, Thomas$$b9
000845779 7001_ $$0P:(DE-HGF)0$$aKögler, Gesine$$b10
000845779 7001_ $$0P:(DE-HGF)0$$aKrieg, Andreas$$b11
000845779 7001_ $$0P:(DE-HGF)0$$aLüdeke, Steffen$$b12
000845779 7001_ $$0P:(DE-HGF)0$$aKunkel, Hana$$b13
000845779 7001_ $$0P:(DE-HGF)0$$aRodrigues Moita, Ana J.$$b14
000845779 7001_ $$0P:(DE-HGF)0$$aKassack, Matthias U.$$b15
000845779 7001_ $$0P:(DE-HGF)0$$aMarquardt, Viktoria$$b16
000845779 7001_ $$0P:(DE-HGF)0$$aOpitz, Friederike V.$$b17
000845779 7001_ $$0P:(DE-HGF)0$$aOldenburg, Marina$$b18
000845779 7001_ $$0P:(DE-HGF)0$$aRemke, Marc$$b19
000845779 7001_ $$0P:(DE-HGF)0$$aBabor, Florian$$b20
000845779 7001_ $$0P:(DE-HGF)0$$aGrez, Manuel$$b21
000845779 7001_ $$0P:(DE-HGF)0$$aHochhaus, Andreas$$b22
000845779 7001_ $$0P:(DE-HGF)0$$aBorkhardt, Arndt$$b23
000845779 7001_ $$0P:(DE-HGF)0$$aGroth, Georg$$b24
000845779 7001_ $$0P:(DE-Juel1)162443$$aNagel-Steger, Luitgard$$b25$$ufzj
000845779 7001_ $$0P:(DE-HGF)0$$aJose, Joachim$$b26
000845779 7001_ $$0P:(DE-HGF)0$$aKurz, Thomas$$b27
000845779 7001_ $$0P:(DE-Juel1)172663$$aGohlke, Holger$$b28$$ufzj
000845779 7001_ $$0P:(DE-HGF)0$$aHansen, Finn K.$$b29$$eCorresponding author
000845779 7001_ $$0P:(DE-HGF)0$$aHauer, Julia$$b30$$eCorresponding author
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