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Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders.

Puleo DE, Kucera K, Hammarén HM, Ungureanu D, Newton AS, Silvennoinen O, Jorgensen WL, Schlessinger J
ACS Med Chem Lett 8 618-621 (2017)
Related entries: 5usz, 5ut0, 5ut1, 5ut2, 5ut3

Cited: 20 times
EuropePMC logo PMID: 28626521

Abstract

Janus kinases (JAKs) regulate hematopoiesis via the cytokine-mediated JAK-STAT signaling pathway. JAKs contain tandem C-terminal pseudokinase (JH2) and tyrosine kinase (JH1) domains. The JAK2 pseudokinase domain adopts a protein kinase fold and, despite its pseudokinase designation, binds ATP with micromolar affinity. Recent evidence shows that displacing ATP from the JAK2 JH2 domain alters the hyperactivation state of the oncogenic JAK2 V617F protein while sparing the wild type JAK2 protein. In this study, small molecule binders of JAK2 JH2 were identified via an in vitro screen. Top hits were characterized using biophysical and structural approaches. Development of pseudokinase-selective compounds may offer novel pharmacological opportunities for treating cancers driven by JAK2 V617F and other oncogenic JAK mutants.

Articles - 5usy mentioned but not cited (4)

  1. Selective Janus Kinase 2 (JAK2) Pseudokinase Ligands with a Diaminotriazole Core. Liosi ME, Krimmer SG, Newton AS, Dawson TK, Puleo DE, Cutrona KJ, Suzuki Y, Schlessinger J, Jorgensen WL. J Med Chem 63 5324-5340 (2020)
  2. Insights on JAK2 Modulation by Potent, Selective, and Cell-Permeable Pseudokinase-Domain Ligands. Liosi ME, Ippolito JA, Henry SP, Krimmer SG, Newton AS, Cutrona KJ, Olivarez RA, Mohanty J, Schlessinger J, Jorgensen WL. J Med Chem 65 8380-8400 (2022)
  3. Covalent Modification of the JH2 Domain of Janus Kinase 2. Henry SP, Liosi ME, Ippolito JA, Menges F, Newton AS, Schlessinger J, Jorgensen WL. ACS Med Chem Lett 13 1819-1826 (2022)
  4. Discovery of Kinase and Carbonic Anhydrase Dual Inhibitors by Machine Learning Classification and Experiments. Kim MJ, Pandit S, Jee JG. Pharmaceuticals (Basel) 15 236 (2022)


Reviews citing this publication (5)

  1. Janus kinases to jakinibs: from basic insights to clinical practice. Gadina M, Le MT, Schwartz DM, Silvennoinen O, Nakayamada S, Yamaoka K, O'Shea JJ. Rheumatology (Oxford) 58 i4-i16 (2019)
  2. JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders. Vainchenker W, Leroy E, Gilles L, Marty C, Plo I, Constantinescu SN. F1000Res 7 82 (2018)
  3. Prospects for pharmacological targeting of pseudokinases. Kung JE, Jura N. Nat Rev Drug Discov 18 501-526 (2019)
  4. There's more to death than life: Noncatalytic functions in kinase and pseudokinase signaling. Mace PD, Murphy JM. J Biol Chem 296 100705 (2021)
  5. Janus Kinases in Leukemia. Raivola J, Haikarainen T, Abraham BG, Silvennoinen O. Cancers (Basel) 13 800 (2021)

Articles citing this publication (11)

  1. Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells. Foulkes DM, Byrne DP, Yeung W, Shrestha S, Bailey FP, Ferries S, Eyers CE, Keeshan K, Wells C, Drewry DH, Zuercher WJ, Kannan N, Eyers PA. Sci Signal 11 eaat7951 (2018)
  2. JAK2 JH2 Fluorescence Polarization Assay and Crystal Structures for Complexes with Three Small Molecules. Newton AS, Deiana L, Puleo DE, Cisneros JA, Cutrona KJ, Schlessinger J, Jorgensen WL. ACS Med Chem Lett 8 614-617 (2017)
  3. Analyzing Resistance to Design Selective Chemical Inhibitors for AAA Proteins. Pisa R, Cupido T, Steinman JB, Jones NH, Kapoor TM. Cell Chem Biol 26 1263-1273.e5 (2019)
  4. Metadynamics as a Postprocessing Method for Virtual Screening with Application to the Pseudokinase Domain of JAK2. Cutrona KJ, Newton AS, Krimmer SG, Tirado-Rives J, Jorgensen WL. J Chem Inf Model 60 4403-4415 (2020)
  5. Indoloxytriazines as binding molecules for the JAK2 JH2 pseudokinase domain and its V617F variant. Newton AS, Liosi ME, Henry SP, Deiana L, Faver JC, Krimmer SG, Puleo DE, Schlessinger J, Jorgensen WL. Tetrahedron Lett 77 153248 (2021)
  6. Conversion of a False Virtual Screen Hit into Selective JAK2 JH2 Domain Binders Using Convergent Design Strategies. Henry SP, Liosi ME, Ippolito JA, Cutrona KJ, Krimmer SG, Newton AS, Schlessinger J, Jorgensen WL. ACS Med Chem Lett 13 819-826 (2022)
  7. A novel chemical attack on Notch-mediated transcription by targeting the NACK ATPase. Diluvio G, Kelley TT, Lahiry M, Alvarez-Trotta A, Kolb EM, Shersher E, Astudillo L, Kovall RA, Schürer SC, Capobianco AJ. Mol Ther Oncolytics 28 307-320 (2023)
  8. Identification of Novel Small Molecule Ligands for JAK2 Pseudokinase Domain. Virtanen AT, Haikarainen T, Sampathkumar P, Palmroth M, Liukkonen S, Liu J, Nekhotiaeva N, Hubbard SR, Silvennoinen O. Pharmaceuticals (Basel) 16 75 (2023)
  9. Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches. Nair PC, Piehler J, Tvorogov D, Ross DM, Lopez AF, Gotlib J, Thomas D. Blood Cancer Discov 4 352-364 (2023)
  10. Novel Small Molecule Tyrosine Kinase 2 Pseudokinase Ligands Block Cytokine-Induced TYK2-Mediated Signaling Pathways. Zhou Y, Li X, Shen R, Wang X, Zhang F, Liu S, Li D, Liu J, Li P, Yan Y, Dong P, Zhang Z, Wu H, Zhuang L, Chowdhury R, Miller M, Issa M, Mao Y, Chen H, Feng J, Li J, Bai C, He F, Tao W. Front Immunol 13 884399 (2022)
  11. Role of water in the determination of protonation states of titratable residues. Zia SR. J Mol Model 27 61 (2021)


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