New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation

Matthew L. Arwood; Yao Liu; Shannon K. Harkins; David M. Weinstock; Lei Yang; Kristen E. Stevenson; Olivia D. Plana; Jingyun Dong; Haley Cirka; Kristen L. Jones; Anniina T. Virtanen; Dikshat G. Gupta; Amanda Ceas; Brian Lawney; Akinori Yoda; Catharine Leahy; Mingfeng Hao; Zhixiang He; Hwan Geun Choi; Yaning Wang; Olli Silvennoinen; Stevan R. Hubbard; Tinghu Zhang; Nathanael S. Gray; Loretta S. Li

doi:10.1016/j.chembiol.2023.05.007

New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation

Matthew L. Arwood, Yao Liu, Shannon K. Harkins, David M. Weinstock, Lei Yang, Kristen E. Stevenson, Olivia D. Plana, Jingyun Dong, Haley Cirka, Kristen L. Jones, Anniina T. Virtanen, Dikshat G. Gupta, Amanda Ceas, Brian Lawney, Akinori Yoda, Catharine Leahy, Mingfeng Hao, Zhixiang He, Hwan Geun Choi, Yaning WangOlli Silvennoinen, Stevan R. Hubbard, Tinghu Zhang, Nathanael S. Gray, Loretta S. Li

Tutkimustuotos: Artikkeli › Tieteellinen › vertaisarvioitu

3 Sitaatiot (Scopus)

Abstrakti

Recurrent JAK2 alterations are observed in myeloproliferative neoplasms, B-cell acute lymphoblastic leukemia, and other hematologic malignancies. Currently available type I JAK2 inhibitors have limited activity in these diseases. Preclinical data support the improved efficacy of type II JAK2 inhibitors, which lock the kinase in the inactive conformation. By screening small molecule libraries, we identified a lead compound with JAK2 selectivity. We highlight analogs with on-target biochemical and cellular activity and demonstrate in vivo activity using a mouse model of polycythemia vera. We present a co-crystal structure that confirms the type II binding mode of our compounds with the “DFG-out” conformation of the JAK2 activation loop. Finally, we identify a JAK2 G993A mutation that confers resistance to the type II JAK2 inhibitor CHZ868 but not to our analogs. These data provide a template for identifying novel type II kinase inhibitors and inform further development of agents targeting JAK2 that overcome resistance.

Alkuperäiskieli	Englanti
Sivut	618-631.e12
Julkaisu	Cell chemical biology
Vuosikerta	30
Numero	6
DOI - pysyväislinkit	https://doi.org/10.1016/j.chembiol.2023.05.007
Tila	Julkaistu - 15 kesäk. 2023
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Julkaisufoorumi-taso

Jufo-taso 2

!!ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

Pääsy asiakirjaan

10.1016/j.chembiol.2023.05.007

Crystal structure of JAK2 JH1 with type II inhibitor YLIU-04-105-1
Arwood, M. L. (Creator), Liu, Y. (Creator), Harkins, S. K. (Creator), Weinstock, D. M. (Creator), Yang, L. (Creator), Stevenson, K. E. (Creator), Plana, O. D. (Creator), Dong, J. (Creator), Cirka, H. (Creator), Jones, K. L. (Creator), Virtanen, A. T. (Creator), Gupta, D. G. (Creator), Ceas, A. (Creator), Lawney, B. (Creator), Yoda, A. (Creator), Leahy, C. (Creator), Hao, M. (Creator), He, Z. (Creator), Choi, H. G. (Creator), Wang, Y. (Creator), Silvennoinen, O. (Creator), Hubbard, S. R. (Creator), Zhang, T. (Creator), Gray, N. S. (Creator) & Li, L. S. (Creator), Protein Data Bank (PDB), 21 kesäk. 2023
DOI - pysyväislinkki: 10.2210/pdb7TEU/pdb
Tietoaineisto: Dataset

Siteeraa tätä

Arwood, M. L., Liu, Y., Harkins, S. K., Weinstock, D. M., Yang, L., Stevenson, K. E., Plana, O. D., Dong, J., Cirka, H., Jones, K. L., Virtanen, A. T., Gupta, D. G., Ceas, A., Lawney, B., Yoda, A., Leahy, C., Hao, M., He, Z., Choi, H. G., ... Li, L. S. (2023). New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation. Cell chemical biology, 30(6), 618-631.e12. https://doi.org/10.1016/j.chembiol.2023.05.007

@article{f6980f80fea64cc8ac522dd12de429c7,

title = "New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation",

abstract = "Recurrent JAK2 alterations are observed in myeloproliferative neoplasms, B-cell acute lymphoblastic leukemia, and other hematologic malignancies. Currently available type I JAK2 inhibitors have limited activity in these diseases. Preclinical data support the improved efficacy of type II JAK2 inhibitors, which lock the kinase in the inactive conformation. By screening small molecule libraries, we identified a lead compound with JAK2 selectivity. We highlight analogs with on-target biochemical and cellular activity and demonstrate in vivo activity using a mouse model of polycythemia vera. We present a co-crystal structure that confirms the type II binding mode of our compounds with the “DFG-out” conformation of the JAK2 activation loop. Finally, we identify a JAK2 G993A mutation that confers resistance to the type II JAK2 inhibitor CHZ868 but not to our analogs. These data provide a template for identifying novel type II kinase inhibitors and inform further development of agents targeting JAK2 that overcome resistance.",

keywords = "B-ALL, CHZ868, CRLF2, JAK2, kinase, myeloproliferative neoplasm, resistance, ruxolitinib, type II inhibitor",

author = "Arwood, {Matthew L.} and Yao Liu and Harkins, {Shannon K.} and Weinstock, {David M.} and Lei Yang and Stevenson, {Kristen E.} and Plana, {Olivia D.} and Jingyun Dong and Haley Cirka and Jones, {Kristen L.} and Virtanen, {Anniina T.} and Gupta, {Dikshat G.} and Amanda Ceas and Brian Lawney and Akinori Yoda and Catharine Leahy and Mingfeng Hao and Zhixiang He and Choi, {Hwan Geun} and Yaning Wang and Olli Silvennoinen and Hubbard, {Stevan R.} and Tinghu Zhang and Gray, {Nathanael S.} and Li, {Loretta S.}",

note = "Funding Information: This work was supported by: the Prostate Cancer Foundation (N.S.G., S.R.H., O.S., and D.M.W.), the Damon Runyon Physician-Scientist Training Award (L.S.L.), CureSearch for Children{\textquoteright}s Cancer (L.S.L.), the Rally! Foundation for Childhood Cancer Research (L.S.L.), a Conquer Cancer Young Investigator Award funded by the Strike 3 Foundation (L.S.L.), an Institutional Research Grant , IRG-21-144-27 , from the American Cancer Society (L.S.L.), the Stanley Manne Children{\textquoteright}s Research Institute and the Ann & Robert H. Lurie Children{\textquoteright}s Hospital of Chicago (L.S.L.), Academy of Finland (A.T.V. and O.S.), Sigrid Jus{\'e}lius Foundation (A.T.V. and O.S.), Cancer Foundation Finland (A.T.V. and O.S.), Jane and Aatos Erkko Foundation (A.T.V. and O.S.), Tampere Tuberculosis Foundation (A.T.V. and O.S.), and Pirkanmaa hospital district competitive research funding (A.T.V. and O.S.). We thank the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, IL for the use of the Flow Cytometry Core Facility. The Lurie Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA060553. The authors thank Renee Rubio from the Dana-Farber Cancer Institute Center for Cancer Computational Biology for technical assistance with the RNA sequencing. Portions of the graphical abstract (QQ23JH07KJ) and Figure 4 A (KO23JGZX77) were created with BioRender.com . Publisher Copyright: {\textcopyright} 2023 Elsevier Ltd",

year = "2023",

month = jun,

day = "15",

doi = "10.1016/j.chembiol.2023.05.007",

language = "English",

volume = "30",

pages = "618--631.e12",

number = "6",

}

Arwood, ML, Liu, Y, Harkins, SK, Weinstock, DM, Yang, L, Stevenson, KE, Plana, OD, Dong, J, Cirka, H, Jones, KL, Virtanen, AT, Gupta, DG, Ceas, A, Lawney, B, Yoda, A, Leahy, C, Hao, M, He, Z, Choi, HG, Wang, Y, Silvennoinen, O, Hubbard, SR, Zhang, T, Gray, NS & Li, LS 2023, 'New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation', Cell chemical biology, Vuosikerta 30, Nro 6, Sivut 618-631.e12. https://doi.org/10.1016/j.chembiol.2023.05.007

TY - JOUR

T1 - New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation

AU - Arwood, Matthew L.

AU - Liu, Yao

AU - Harkins, Shannon K.

AU - Weinstock, David M.

AU - Yang, Lei

AU - Stevenson, Kristen E.

AU - Plana, Olivia D.

AU - Dong, Jingyun

AU - Cirka, Haley

AU - Jones, Kristen L.

AU - Virtanen, Anniina T.

AU - Gupta, Dikshat G.

AU - Ceas, Amanda

AU - Lawney, Brian

AU - Yoda, Akinori

AU - Leahy, Catharine

AU - Hao, Mingfeng

AU - He, Zhixiang

AU - Choi, Hwan Geun

AU - Wang, Yaning

AU - Silvennoinen, Olli

AU - Hubbard, Stevan R.

AU - Zhang, Tinghu

AU - Gray, Nathanael S.

AU - Li, Loretta S.

N1 - Funding Information: This work was supported by: the Prostate Cancer Foundation (N.S.G., S.R.H., O.S., and D.M.W.), the Damon Runyon Physician-Scientist Training Award (L.S.L.), CureSearch for Children’s Cancer (L.S.L.), the Rally! Foundation for Childhood Cancer Research (L.S.L.), a Conquer Cancer Young Investigator Award funded by the Strike 3 Foundation (L.S.L.), an Institutional Research Grant , IRG-21-144-27 , from the American Cancer Society (L.S.L.), the Stanley Manne Children’s Research Institute and the Ann & Robert H. Lurie Children’s Hospital of Chicago (L.S.L.), Academy of Finland (A.T.V. and O.S.), Sigrid Jusélius Foundation (A.T.V. and O.S.), Cancer Foundation Finland (A.T.V. and O.S.), Jane and Aatos Erkko Foundation (A.T.V. and O.S.), Tampere Tuberculosis Foundation (A.T.V. and O.S.), and Pirkanmaa hospital district competitive research funding (A.T.V. and O.S.). We thank the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, IL for the use of the Flow Cytometry Core Facility. The Lurie Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA060553. The authors thank Renee Rubio from the Dana-Farber Cancer Institute Center for Cancer Computational Biology for technical assistance with the RNA sequencing. Portions of the graphical abstract (QQ23JH07KJ) and Figure 4 A (KO23JGZX77) were created with BioRender.com . Publisher Copyright: © 2023 Elsevier Ltd

PY - 2023/6/15

Y1 - 2023/6/15

N2 - Recurrent JAK2 alterations are observed in myeloproliferative neoplasms, B-cell acute lymphoblastic leukemia, and other hematologic malignancies. Currently available type I JAK2 inhibitors have limited activity in these diseases. Preclinical data support the improved efficacy of type II JAK2 inhibitors, which lock the kinase in the inactive conformation. By screening small molecule libraries, we identified a lead compound with JAK2 selectivity. We highlight analogs with on-target biochemical and cellular activity and demonstrate in vivo activity using a mouse model of polycythemia vera. We present a co-crystal structure that confirms the type II binding mode of our compounds with the “DFG-out” conformation of the JAK2 activation loop. Finally, we identify a JAK2 G993A mutation that confers resistance to the type II JAK2 inhibitor CHZ868 but not to our analogs. These data provide a template for identifying novel type II kinase inhibitors and inform further development of agents targeting JAK2 that overcome resistance.

AB - Recurrent JAK2 alterations are observed in myeloproliferative neoplasms, B-cell acute lymphoblastic leukemia, and other hematologic malignancies. Currently available type I JAK2 inhibitors have limited activity in these diseases. Preclinical data support the improved efficacy of type II JAK2 inhibitors, which lock the kinase in the inactive conformation. By screening small molecule libraries, we identified a lead compound with JAK2 selectivity. We highlight analogs with on-target biochemical and cellular activity and demonstrate in vivo activity using a mouse model of polycythemia vera. We present a co-crystal structure that confirms the type II binding mode of our compounds with the “DFG-out” conformation of the JAK2 activation loop. Finally, we identify a JAK2 G993A mutation that confers resistance to the type II JAK2 inhibitor CHZ868 but not to our analogs. These data provide a template for identifying novel type II kinase inhibitors and inform further development of agents targeting JAK2 that overcome resistance.

KW - B-ALL

KW - CHZ868

KW - CRLF2

KW - JAK2

KW - kinase

KW - myeloproliferative neoplasm

KW - resistance

KW - ruxolitinib

KW - type II inhibitor

U2 - 10.1016/j.chembiol.2023.05.007

DO - 10.1016/j.chembiol.2023.05.007

M3 - Article

C2 - 37290440

AN - SCOPUS:85163098688

SN - 2451-9456

VL - 30

SP - 618-631.e12

JO - Cell chemical biology

JF - Cell chemical biology

IS - 6

ER -

New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation

Abstrakti

Julkaisufoorumi-taso

!!ASJC Scopus subject areas

Pääsy asiakirjaan

Sormenjälki

Tietoaineistot

Crystal structure of JAK2 JH1 with type II inhibitor YLIU-04-105-1

Siteeraa tätä