Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors

Zhang, Jianming; Adrián, Francisco; Jahnke, Wolfgang; Cowan‐Jacob, Sandra W.; Li, Allen G.; Iacob, Roxana E.; Sim, Taebo; Powers, John T.; Dierks, Christine; Sun, Fangxian; Guo, Gui Rong; Ding, Qiang; Barun, Okram; Choi, Yongmun; Wojciechowski, Amy; Deng, Xianming; Liu, Guoxun; Fendrich, Gabriele; Strauss, André; Vajpai, Navratna; Grzesiek, Stephan; Tuntland, Tove; Liu, Yi; Bursulaya, Badry; Azam, Mohammad; Manley, Paul W.; Engen, John R.; Daley, George Q.; Warmuth, Markus; Gray, Nathanael S.

doi:10.1038/nature08675

Cited by 545 publications

(609 citation statements)

References 41 publications

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“…Two recently approved drugs nilotinib and dasatinib are able to override the majority of the imatinib resistance mutations with the exception of T315I mutation, which is situated in the middle of the ATP-binding cleft [6][7][8][9][10][11][12] . GNF-2, a selective allosteric Bcr-Abl inhibitor, is new pharmacological modality to overcome resistance to ATP-site inhibitors of BcrAbl [13,14] . GNF-2 binds to the myristate binding site of Abl, leading to changes in the structural dynamics of the ATPbinding site.…”

Section: Introductionmentioning

confidence: 99%

Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro

Wāng

Chen

et al. 2014

Acta Pharmacol Sin

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Aim: To find new kinase inhibitors that overcome the imatinib resistance in treatment of chronic myeloid leukemia (CML), we synthesized C817, a novel derivative of curcumin, and tested its activities against wild-type (WT) and imatinib-resistant mutant Abl kinases, as well as in imatinib-sensitive and resistant CML cells in vitro. Methods: 32D cells harboring WT or mutant Abl kinases (nucleotide binding P-loop mutants Q252H, Y253F, and imatinib contact residue mutant T315I), as well as K562/G01 cells (with whole Bcr-Abl gene amplication) were tested. Kinase activity was measured using Kinase-Glo Luminescent Kinase Assay Platform in recombinant WT and mutant (Q252H, Y253F, and T315I) Abl kinases. Cell proliferation and apoptosis were examined using MTT assay and flow cytometry, respectively. The phosphorylation levels of Bcr-Abl initiated signaling proteins were analyzed using Western blotting. Colony forming units (CFU) growth and long term culture-initiating cells (LTC-ICs) were used to test the effects of C817 on human leukemia progenitor/stem cells. Results: C817 potently inhibited both WT and mutant (Q252H, Y253F, and T315I) Abl kinase activities in a non-ATP competitive manner with the values of IC 50 at low nanomole levels. In consistent with above results, C817 suppressed the growth of both imatinib-sensitive and resistant CML cells, including wild-type K562, K562/G01, 32D-T315I, 32D-Q252H, and 32D-Y253F cells with the values of IC 50 at low micromole levels. C817 (0.5 or 1 μmol/L) dose-dependently inhibited the phosphorylation of Bcr-Abl and downstream proteins STAT-5 and CrkL in imatinib-resistant K562/G01 cells. Furthermore, C817 significantly suppressed CFU growth and LTC-ICs, implicating that C817 could eradiate human leukemia progenitor/stem cells. Conclusion: C817 is a promising compound for treatment of CML patients with Bcr-Abl kinase domain mutations that confer imatinib resistance.

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Section: Introductionmentioning

confidence: 99%

Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro

Wāng

Chen

et al. 2014

Acta Pharmacol Sin

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“…Elegante strukturbiologische Arbeiten, welche sowohl Röntgenkristallo-graphie, kernmagnetische Resonanzspektroskopie (NMR) und WasserstoffDeuterium Austauschmassenspektrometrie kombinierten, haben den Wirkmechanismus von GNF-2 und dem Zweitgenerationsinhibitor GNF-5 bestä-tigt [24]. Des Weiteren konnte [2,6,21] gezeigt werden, dass die Kombination von GNF-5 mit dem Zweitgenerationsinhibitor Nilotinib das Überleben in einem Maus-Xenotransplantationsmodell mit BCR-ABL1-T315I-exprimierenden Zellen stark verlängert [24].…”

Section: » Gnf-2 Ist Ein Nicht Atpkompetitiver Allosterischer Inhibitorunclassified

“…Des Weiteren konnte [2,6,21] gezeigt werden, dass die Kombination von GNF-5 mit dem Zweitgenerationsinhibitor Nilotinib das Überleben in einem Maus-Xenotransplantationsmodell mit BCR-ABL1-T315I-exprimierenden Zellen stark verlängert [24]. In diesem Modell zeigt die Einzeltherapie mit beiden Medikamenten keine Wirkung.…”

Section: » Gnf-2 Ist Ein Nicht Atpkompetitiver Allosterischer Inhibitorunclassified

Allosterische Kinaseinhibitoren

Hantschel

Ottmann

2017

Onkologe

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Für die Pathogenese der CML und der Philadelphia(Ph)-Chromosom-positiven akuten lymphatischen Leukämie (Ph + -ALL) ist die gesteigerte Kinaseaktivität des BCR-ABL1-Fusionsonkoproteins von zentraler Bedeutung. Die Hemmung der BCR-ABL1-Kinase, z. B. durch Imatinib, hat zu einem Langzeitüberleben der CML-Patienten von über 80 % geführt [9,10]. Bei der Ph + -ALL erreichen mit Imatinib als Erstlinientherapie mehr als 90 % der Patienten zumindest initial eine komplette Remission. Während bei der Ph + -ALL das Problem der Resistenzentwicklung aufgrund von Mutationen der BCR-ABLKinase-Domäne klinisch dominiert [5], richtet sich bei der CML das Hauptaugenmerk mittlerweile auf das Erreichen von Therapiefreiheit [3,20]. Diese Problematik hat sich mit der Entwicklung potenterer TKI der zweiten Generation nicht grundlegend geändert [18]. Hierauf begründet sich die Rationale für die Entwicklung neuer hochpotenter allosterischer BCR-ABL1-Inhibitoren, die für eine Kombinationstherapie mit konventionellen katalytischen TKI geeignet sind, keine Kreuzresistenz mit diesen zeigen und ein gutes Verträglichkeitsprofil aufweisen.

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“…17,25,26 Briefly, the peritoneal exudate cells were washed twice with cold Hanks' solution and adjusted to 5310 6 cells/ml in RPMI 1640 medium (Gibco BRL, Grand Island, NY, USA). The cells were cultured in 2% gelatin (Sigma, St Louis, MO, USA)-pretreated six-well plates (Costar, Cambridge, MA, USA) for 3-4 h at 37 uC and 5% CO 2 .…”

Section: Preparation Of Peritoneal Macrophagesmentioning

confidence: 99%

“…15 Bone marrow transplantation is used in clinics to treat patients with leukemia or other relevant diseases. 16,17 However, graft-versus-host disease remains a major barrier for the clinical application of HLAmismatched bone marrow transplantation. [18][19][20] The protective effect of donor CD4 1 CD25 1 Tregs in graft-versus-host disease has been previously demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Induction of M2-like macrophages in recipient NOD-scid mice by allogeneic donor CD4+CD25+ regulatory T cells

Liu

Hou

et al. 2012

Cell Mol Immunol

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CD4 1 CD25 1 regulatory T cells (Tregs) play an important role in maintaining host immune tolerance via regulation of the phenotype and function of the innate and adaptive immune cells. Whether allogeneic CD4 1 CD25 1 Tregs can regulate recipient mouse macrophages is unknown. The effect of allogeneic donor CD4 1 CD25 1 Tregs on recipient mouse resident F4/80 1 macrophages was investigated using a mouse model in which allogeneic donor CD4 1 CD25 1 Tregs were adoptively transferred into the peritoneal cavity of host NOD-scid mice. The phenotype and function of the recipient macrophages were then assayed. The peritoneal F4/80 1 macrophages in the recipient mice that received the allogeneic CD4 1 CD25 1 Tregs expressed significantly higher levels of CD23 and programmed cell death-ligand 1(PD-L1) and lower levels of CD80, CD86, CD40 and MHC II molecules compared to the mice that received either allogeneic CD4 1 CD25 2 T cells (Teffs) or no cells. The resident F4/80 1 macrophages of the recipient mice injected with the allogeneic donor CD4 1 CD25 1 Tregs displayed significantly increased phagocytosis of chicken red blood cells (cRBCs) and arginase activity together with increased IL-10 production, whereas these macrophages also showed decreased immunogenicity and nitric oxide (NO) production. Blocking arginase partially but significantly reversed the effects of CD4 1 CD25 1 Tregs with regard to the induction of the M2 macrophages in vivo. Therefore, the allogeneic donor CD4 1 CD25 1 Tregs can induce the M2 macrophages in recipient mice at least in part via an arginase pathway. We have provided in vivo evidence to support the unknown pathways by which allogeneic donor CD4 1 CD25 1 Tregs regulate innate immunity in recipient mice by promoting the differentiation of M2 macrophages.

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Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors

Cited by 545 publications

References 41 publications

Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro

Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro

Allosterische Kinaseinhibitoren

Induction of M2-like macrophages in recipient NOD-scid mice by allogeneic donor CD4+CD25+ regulatory T cells

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