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CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.

Abstract Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells,?murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title cancer cell
Publication Year Start
%A Meyer, Sara C.; Keller, Matthew D.; Chiu, Sophia; Koppikar, Priya; Guryanova, Olga A.; Rapaport, Franck; Xu, Ke; Manova, Katia; Pankov, Dmitry; O'Reilly, Richard J.; Kleppe, Maria; McKenney, Anna Sophia; Shih, Alan H.; Shank, Kaitlyn; Ahn, Jihae; Papalexi, Eftymia; Spitzer, Barbara; Socci, Nick; Viale, Agnes; Mandon, Emeline; Ebel, Nicolas; Andraos, Rita; Rubert, Jo?lle; Dammassa, Ernesta; Romanet, Vincent; D?lemeyer, Arno; Zender, Michael; Heinlein, Melanie; Rampal, Raajit; Weinberg, Rona Singer; Hoffman, Ronald; Sellers, William R.; Hofmann, Francesco; Murakami, Masato; Baffert, Fabienne; Gaul, Christoph; Radimerski, Thomas; Levine, Ross L.
%T CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.
%J Cancer cell, vol. 28, no. 1, pp. 15-28
%D 07/2015
%V 28
%N 1
%M eng
%B Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells,?murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients.
%K Animals, Antineoplastic Agents, Benzamides, Cell Line, Tumor, Cell Proliferation, Humans, Janus Kinase 2, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Mutation, Myeloproliferative Disorders, Protein Kinase Inhibitors, Pyrimidines, Receptors, Thrombopoietin, Sequence Analysis, RNA, Signal Transduction, Xenograft Model Antitumor Assays
%P 15
%L 28
%Y 10.1016/j.ccell.2015.06.006
%W PHY
%G AUTHOR
%R 2015.......28...15M

@Article{Meyer2015,
author="Meyer, Sara C.
and Keller, Matthew D.
and Chiu, Sophia
and Koppikar, Priya
and Guryanova, Olga A.
and Rapaport, Franck
and Xu, Ke
and Manova, Katia
and Pankov, Dmitry
and O'Reilly, Richard J.
and Kleppe, Maria
and McKenney, Anna Sophia
and Shih, Alan H.
and Shank, Kaitlyn
and Ahn, Jihae
and Papalexi, Eftymia
and Spitzer, Barbara
and Socci, Nick
and Viale, Agnes
and Mandon, Emeline
and Ebel, Nicolas
and Andraos, Rita
and Rubert, Jo{\"e}lle
and Dammassa, Ernesta
and Romanet, Vincent
and D{\"o}lemeyer, Arno
and Zender, Michael
and Heinlein, Melanie
and Rampal, Raajit
and Weinberg, Rona Singer
and Hoffman, Ronald
and Sellers, William R.
and Hofmann, Francesco
and Murakami, Masato
and Baffert, Fabienne
and Gaul, Christoph
and Radimerski, Thomas
and Levine, Ross L.",
title="CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.",
journal="Cancer cell",
year="2015",
month="Jul",
day="13",
volume="28",
number="1",
pages="15--28",
keywords="Animals",
keywords="Antineoplastic Agents",
keywords="Benzamides",
keywords="Cell Line, Tumor",
keywords="Cell Proliferation",
keywords="Humans",
keywords="Janus Kinase 2",
keywords="Mice",
keywords="Mice, Inbred C57BL",
keywords="Molecular Sequence Data",
keywords="Mutation",
keywords="Myeloproliferative Disorders",
keywords="Protein Kinase Inhibitors",
keywords="Pyrimidines",
keywords="Receptors, Thrombopoietin",
keywords="Sequence Analysis, RNA",
keywords="Signal Transduction",
keywords="Xenograft Model Antitumor Assays",
abstract="Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells,?murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients.",
issn="1878-3686",
doi="10.1016/j.ccell.2015.06.006",
url="http://www.ncbi.nlm.nih.gov/pubmed/26175413",
language="eng"
}

%0 Journal Article
%T CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.
%A Meyer, Sara C.
%A Keller, Matthew D.
%A Chiu, Sophia
%A Koppikar, Priya
%A Guryanova, Olga A.
%A Rapaport, Franck
%A Xu, Ke
%A Manova, Katia
%A Pankov, Dmitry
%A O'Reilly, Richard J.
%A Kleppe, Maria
%A McKenney, Anna Sophia
%A Shih, Alan H.
%A Shank, Kaitlyn
%A Ahn, Jihae
%A Papalexi, Eftymia
%A Spitzer, Barbara
%A Socci, Nick
%A Viale, Agnes
%A Mandon, Emeline
%A Ebel, Nicolas
%A Andraos, Rita
%A Rubert, Jo?lle
%A Dammassa, Ernesta
%A Romanet, Vincent
%A D?lemeyer, Arno
%A Zender, Michael
%A Heinlein, Melanie
%A Rampal, Raajit
%A Weinberg, Rona Singer
%A Hoffman, Ronald
%A Sellers, William R.
%A Hofmann, Francesco
%A Murakami, Masato
%A Baffert, Fabienne
%A Gaul, Christoph
%A Radimerski, Thomas
%A Levine, Ross L.
%J Cancer cell
%D 2015
%8 Jul 13
%V 28
%N 1
%@ 1878-3686
%G eng
%F Meyer2015
%X Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells,?murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients.
%K Animals
%K Antineoplastic Agents
%K Benzamides
%K Cell Line, Tumor
%K Cell Proliferation
%K Humans
%K Janus Kinase 2
%K Mice
%K Mice, Inbred C57BL
%K Molecular Sequence Data
%K Mutation
%K Myeloproliferative Disorders
%K Protein Kinase Inhibitors
%K Pyrimidines
%K Receptors, Thrombopoietin
%K Sequence Analysis, RNA
%K Signal Transduction
%K Xenograft Model Antitumor Assays
%U http://dx.doi.org/10.1016/j.ccell.2015.06.006
%U http://www.ncbi.nlm.nih.gov/pubmed/26175413
%P 15-28

PT Journal
AU Meyer, SC
   Keller, MD
   Chiu, S
   Koppikar, P
   Guryanova, OA
   Rapaport, F
   Xu, K
   Manova, K
   Pankov, D
   O'Reilly, RJ
   Kleppe, M
   McKenney, AS
   Shih, AH
   Shank, K
   Ahn, J
   Papalexi, E
   Spitzer, B
   Socci, N
   Viale, A
   Mandon, E
   Ebel, N
   Andraos, R
   Rubert, J
   Dammassa, E
   Romanet, V
   D?lemeyer, A
   Zender, M
   Heinlein, M
   Rampal, R
   Weinberg, RS
   Hoffman, R
   Sellers, WR
   Hofmann, F
   Murakami, M
   Baffert, F
   Gaul, C
   Radimerski, T
   Levine, RL
TI CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.
SO Cancer cell
JI Cancer Cell
PD Jul
PY 2015
BP 15
EP 28
VL 28
IS 1
DI 10.1016/j.ccell.2015.06.006
LA eng
DE Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Proliferation; Humans; Janus Kinase 2; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Mutation; Myeloproliferative Disorders; Protein Kinase Inhibitors; Pyrimidines; Receptors, Thrombopoietin; Sequence Analysis, RNA; Signal Transduction; Xenograft Model Antitumor Assays
AB Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells,?murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients.
ER

PMID- 26175413
OWN - NLM
STAT- MEDLINE
DA  - 20150715
DCOM- 20151013
LR  - 20160805
IS  - 1878-3686 (Electronic)
IS  - 1535-6108 (Linking)
VI  - 28
IP  - 1
DP  - 2015 Jul 13
TI  - CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and
      Demonstrates Efficacy in Myeloproliferative Neoplasms.
PG  - 15-28
LID - 10.1016/j.ccell.2015.06.006 [doi]
LID - S1535-6108(15)00216-0 [pii]
AB  - Although clinically tested JAK inhibitors reduce splenomegaly and systemic
      symptoms, molecular responses are not observed in most myeloproliferative
      neoplasm (MPN) patients. We previously demonstrated that MPN cells become
      persistent to type I JAK inhibitors that bind the active conformation of JAK2. We
      investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity 
      in JAK inhibitor persistent cells, murine MPN models, and MPN patient samples.
      JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK
      inhibitor persistent cells. CHZ868 showed significant activity in murine MPN
      models and induced reductions in mutant allele burden not observed with type I
      JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable
      therapeutic approach for MPN patients.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Meyer, Sara C
AU  - Meyer SC
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA.
FAU - Keller, Matthew D
AU  - Keller MD
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA.
FAU - Chiu, Sophia
AU  - Chiu S
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA.
FAU - Koppikar, Priya
AU  - Koppikar P
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA.
FAU - Guryanova, Olga A
AU  - Guryanova OA
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA.
FAU - Rapaport, Franck
AU  - Rapaport F
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA.
FAU - Xu, Ke
AU  - Xu K
AD  - Molecular Cytology, Memorial Sloan Kettering Cancer Center, New York, NY 10065,
      USA.
FAU - Manova, Katia
AU  - Manova K
AD  - Molecular Cytology, Memorial Sloan Kettering Cancer Center, New York, NY 10065,
      USA.
FAU - Pankov, Dmitry
AU  - Pankov D
AD  - Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
      10065, USA.
FAU - O'Reilly, Richard J
AU  - O'Reilly RJ
AD  - Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
      10065, USA.
FAU - Kleppe, Maria
AU  - Kleppe M
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA.
FAU - McKenney, Anna Sophia
AU  - McKenney AS
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA.
FAU - Shih, Alan H
AU  - Shih AH
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA.
FAU - Shank, Kaitlyn
AU  - Shank K
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA.
FAU - Ahn, Jihae
AU  - Ahn J
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA.
FAU - Papalexi, Eftymia
AU  - Papalexi E
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA.
FAU - Spitzer, Barbara
AU  - Spitzer B
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA.
FAU - Socci, Nick
AU  - Socci N
AD  - Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, 
      NY 10065, USA.
FAU - Viale, Agnes
AU  - Viale A
AD  - Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, 
      NY 10065, USA.
FAU - Mandon, Emeline
AU  - Mandon E
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
FAU - Ebel, Nicolas
AU  - Ebel N
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
FAU - Andraos, Rita
AU  - Andraos R
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
FAU - Rubert, Joelle
AU  - Rubert J
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
FAU - Dammassa, Ernesta
AU  - Dammassa E
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
FAU - Romanet, Vincent
AU  - Romanet V
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
FAU - Dolemeyer, Arno
AU  - Dolemeyer A
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
FAU - Zender, Michael
AU  - Zender M
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
FAU - Heinlein, Melanie
AU  - Heinlein M
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
FAU - Rampal, Raajit
AU  - Rampal R
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan
      Kettering Cancer Center, New York, NY 10065, USA.
FAU - Weinberg, Rona Singer
AU  - Weinberg RS
AD  - New York Blood Center, New York, NY 10065, USA.
FAU - Hoffman, Ronald
AU  - Hoffman R
AD  - Department of Medicine, Mount Sinai Hospital, New York, NY 10029, USA.
FAU - Sellers, William R
AU  - Sellers WR
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Hofmann, Francesco
AU  - Hofmann F
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
FAU - Murakami, Masato
AU  - Murakami M
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
FAU - Baffert, Fabienne
AU  - Baffert F
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
FAU - Gaul, Christoph
AU  - Gaul C
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
FAU - Radimerski, Thomas
AU  - Radimerski T
AD  - Novartis Institutes for Biomedical Research, Basel 4056, Switzerland. Electronic 
      address: [email protected]
FAU - Levine, Ross L
AU  - Levine RL
AD  - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 
      New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan
      Kettering Cancer Center, New York, NY 10065, USA. Electronic address:
      [email protected]
LA  - eng
SI  - GEO/GSE69827
GR  - 1K99CA178191/CA/NCI NIH HHS/United States
GR  - 1R01CA151949-01/CA/NCI NIH HHS/United States
GR  - 5F30CA183497/CA/NCI NIH HHS/United States
GR  - F30 CA183497/CA/NCI NIH HHS/United States
GR  - K08 CA188529/CA/NCI NIH HHS/United States
GR  - K99 CA178191/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - R01 CA151949/CA/NCI NIH HHS/United States
GR  - T32GM007739/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Cancer Cell
JT  - Cancer cell
JID - 101130617
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzamides)
RN  - 0 (N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - 0 (Receptors, Thrombopoietin)
RN  - 143641-95-6 (MPL protein, human)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
CIN - Cancer Cell. 2015 Jul 13;28(1):1-2. PMID: 26175407
MH  - Animals
MH  - Antineoplastic Agents/*administration & dosage/pharmacology
MH  - Benzamides/administration & dosage
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Humans
MH  - Janus Kinase 2/*antagonists & inhibitors/*genetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Myeloproliferative Disorders/*drug therapy/genetics/metabolism
MH  - Protein Kinase Inhibitors/*administration & dosage/pharmacology
MH  - Pyrimidines/administration & dosage
MH  - Receptors, Thrombopoietin/genetics/metabolism
MH  - Sequence Analysis, RNA
MH  - Signal Transduction/drug effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC4503933
MID - NIHMS705062
OID - NLM: NIHMS705062
OID - NLM: PMC4503933
EDAT- 2015/07/16 06:00
MHDA- 2015/10/16 06:00
CRDT- 2015/07/16 06:00
PHST- 2014/11/03 [received]
PHST- 2015/05/05 [revised]
PHST- 2015/06/14 [accepted]
AID - S1535-6108(15)00216-0 [pii]
AID - 10.1016/j.ccell.2015.06.006 [doi]
PST - ppublish
SO  - Cancer Cell. 2015 Jul 13;28(1):15-28. doi: 10.1016/j.ccell.2015.06.006.
TY  - JOUR
AU  - Meyer, Sara C.
AU  - Keller, Matthew D.
AU  - Chiu, Sophia
AU  - Koppikar, Priya
AU  - Guryanova, Olga A.
AU  - Rapaport, Franck
AU  - Xu, Ke
AU  - Manova, Katia
AU  - Pankov, Dmitry
AU  - O'Reilly, Richard J.
AU  - Kleppe, Maria
AU  - McKenney, Anna Sophia
AU  - Shih, Alan H.
AU  - Shank, Kaitlyn
AU  - Ahn, Jihae
AU  - Papalexi, Eftymia
AU  - Spitzer, Barbara
AU  - Socci, Nick
AU  - Viale, Agnes
AU  - Mandon, Emeline
AU  - Ebel, Nicolas
AU  - Andraos, Rita
AU  - Rubert, Jo?lle
AU  - Dammassa, Ernesta
AU  - Romanet, Vincent
AU  - D?lemeyer, Arno
AU  - Zender, Michael
AU  - Heinlein, Melanie
AU  - Rampal, Raajit
AU  - Weinberg, Rona Singer
AU  - Hoffman, Ronald
AU  - Sellers, William R.
AU  - Hofmann, Francesco
AU  - Murakami, Masato
AU  - Baffert, Fabienne
AU  - Gaul, Christoph
AU  - Radimerski, Thomas
AU  - Levine, Ross L.
PY  - 2015/Jul/13
TI  - CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.
T2  - Cancer Cell
JO  - Cancer cell
SP  - 15
EP  - 28
VL  - 28
IS  - 1
KW  - Animals
KW  - Antineoplastic Agents
KW  - Benzamides
KW  - Cell Line, Tumor
KW  - Cell Proliferation
KW  - Humans
KW  - Janus Kinase 2
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Molecular Sequence Data
KW  - Mutation
KW  - Myeloproliferative Disorders
KW  - Protein Kinase Inhibitors
KW  - Pyrimidines
KW  - Receptors, Thrombopoietin
KW  - Sequence Analysis, RNA
KW  - Signal Transduction
KW  - Xenograft Model Antitumor Assays
N2  - Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells,?murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients.
SN  - 1878-3686
UR  - http://dx.doi.org/10.1016/j.ccell.2015.06.006
UR  - http://www.ncbi.nlm.nih.gov/pubmed/26175413
ID  - Meyer2015
ER  - 
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<b:Person><b:Last>Shih</b:Last><b:First>Alan</b:First><b:Middle>H</b:Middle></b:Person>
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<b:Person><b:Last>Spitzer</b:Last><b:First>Barbara</b:First></b:Person>
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<b:Person><b:Last>Viale</b:Last><b:First>Agnes</b:First></b:Person>
<b:Person><b:Last>Mandon</b:Last><b:First>Emeline</b:First></b:Person>
<b:Person><b:Last>Ebel</b:Last><b:First>Nicolas</b:First></b:Person>
<b:Person><b:Last>Andraos</b:Last><b:First>Rita</b:First></b:Person>
<b:Person><b:Last>Rubert</b:Last><b:First>Jo&#235;lle</b:First></b:Person>
<b:Person><b:Last>Dammassa</b:Last><b:First>Ernesta</b:First></b:Person>
<b:Person><b:Last>Romanet</b:Last><b:First>Vincent</b:First></b:Person>
<b:Person><b:Last>D&#246;lemeyer</b:Last><b:First>Arno</b:First></b:Person>
<b:Person><b:Last>Zender</b:Last><b:First>Michael</b:First></b:Person>
<b:Person><b:Last>Heinlein</b:Last><b:First>Melanie</b:First></b:Person>
<b:Person><b:Last>Rampal</b:Last><b:First>Raajit</b:First></b:Person>
<b:Person><b:Last>Weinberg</b:Last><b:First>Rona</b:First><b:Middle>Singer</b:Middle></b:Person>
<b:Person><b:Last>Hoffman</b:Last><b:First>Ronald</b:First></b:Person>
<b:Person><b:Last>Sellers</b:Last><b:First>William</b:First><b:Middle>R</b:Middle></b:Person>
<b:Person><b:Last>Hofmann</b:Last><b:First>Francesco</b:First></b:Person>
<b:Person><b:Last>Murakami</b:Last><b:First>Masato</b:First></b:Person>
<b:Person><b:Last>Baffert</b:Last><b:First>Fabienne</b:First></b:Person>
<b:Person><b:Last>Gaul</b:Last><b:First>Christoph</b:First></b:Person>
<b:Person><b:Last>Radimerski</b:Last><b:First>Thomas</b:First></b:Person>
<b:Person><b:Last>Levine</b:Last><b:First>Ross</b:First><b:Middle>L</b:Middle></b:Person>
</b:NameList></b:Author>
</b:Author>
<b:Title>CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.</b:Title>
 <b:ShortTitle>Cancer Cell</b:ShortTitle>
<b:Comments>Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells,&#160;murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients.</b:Comments>
</b:Source>
</b:Sources>