ORCID Profile
0000-0002-2143-2270
Current Organisation
Osnabrück University
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Manufacturing Engineering | Manufacturing Processes and Technologies (excl. Textiles) | Microtechnology
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792303.V1
Abstract: JAK2-PK
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.C.6762722.V1
Abstract: Abstract Selective inhibitors of Janus kinase (JAK) 2 have been in demand since the discovery of the JAK2 V617F mutation present in patients with myeloproliferative neoplasms (MPN) however, the structural basis of V617F oncogenicity has only recently been elucidated. New structural studies reveal a role for other JAK2 domains, beyond the kinase domain, that contribute to pathogenic signaling. Here we evaluate the structure-based approaches that led to recently-approved type I JAK2 inhibitors (fedratinib and pacritinib), as well as type II (BBT594 and CHZ868) and pseudokinase inhibitors under development (JNJ7706621). With full-length JAK homodimeric structures now available, superior selective and mutation-specific JAK2 inhibitors are foreseeable. Significance: The JAK inhibitors currently used for the treatment of MPNs are effective for symptom management but not for disease eradication, primarily because they are not strongly selective for the mutant clone. The rise of computational and structure-based drug discovery approaches together with the knowledge of full-length JAK dimer complexes provides a unique opportunity to develop better targeted therapies for a range of conditions driven by pathologic JAK2 signaling. /
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.BCD-22-0189
Abstract: The JAK inhibitors currently used for the treatment of MPNs are effective for symptom management but not for disease eradication, primarily because they are not strongly selective for the mutant clone. The rise of computational and structure-based drug discovery approaches together with the knowledge of full-length JAK dimer complexes provides a unique opportunity to develop better targeted therapies for a range of conditions driven by pathologic JAK2 signaling.
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792312
Abstract: JAK2-monomer-500ns.pdb. (Structure of human JAK2 monomer at 500 ns simulation).
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792315
Abstract: JAK2-monomer-0ns.pdb. (Model of human JAK2 monomer used for molecular dynamics simulation).
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792303
Abstract: JAK2-PK
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792315.V1
Abstract: JAK2-monomer-0ns.pdb. (Model of human JAK2 monomer used for molecular dynamics simulation).
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792318
Abstract: Figure showing X-ray crystal structure of pseudokinase domain inhibitor
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792309
Abstract: Supplementary Information: Figure S1 X-ray crystal structure of JNJ-77006621(ball and stick, C-atoms in green) bound to JAK2-PK domain (cartoon, yellow). Key residues are displayed in sticks [C-atoms in green near the optimisation domain (Peuleo et al. 2017, Liosi et al 2020) and C-atoms in yellow at the dimerization domain]. Supplementary Methods.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792312.V1
Abstract: JAK2-monomer-500ns.pdb. (Structure of human JAK2 monomer at 500 ns simulation).
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792318.V1
Abstract: Figure showing X-ray crystal structure of pseudokinase domain inhibitor
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
DOI: 10.1158/2643-3230.C.6762722
Abstract: Abstract Selective inhibitors of Janus kinase (JAK) 2 have been in demand since the discovery of the JAK2 V617F mutation present in patients with myeloproliferative neoplasms (MPN) however, the structural basis of V617F oncogenicity has only recently been elucidated. New structural studies reveal a role for other JAK2 domains, beyond the kinase domain, that contribute to pathogenic signaling. Here we evaluate the structure-based approaches that led to recently-approved type I JAK2 inhibitors (fedratinib and pacritinib), as well as type II (BBT594 and CHZ868) and pseudokinase inhibitors under development (JNJ7706621). With full-length JAK homodimeric structures now available, superior selective and mutation-specific JAK2 inhibitors are foreseeable. Significance: The JAK inhibitors currently used for the treatment of MPNs are effective for symptom management but not for disease eradication, primarily because they are not strongly selective for the mutant clone. The rise of computational and structure-based drug discovery approaches together with the knowledge of full-length JAK dimer complexes provides a unique opportunity to develop better targeted therapies for a range of conditions driven by pathologic JAK2 signaling. /
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792309.V1
Abstract: Supplementary Information: Figure S1 X-ray crystal structure of JNJ-77006621(ball and stick, C-atoms in green) bound to JAK2-PK domain (cartoon, yellow). Key residues are displayed in sticks [C-atoms in green near the optimisation domain (Peuleo et al. 2017, Liosi et al 2020) and C-atoms in yellow at the dimerization domain]. Supplementary Methods.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Start Date: 06-2020
End Date: 09-2023
Amount: $550,000.00
Funder: Australian Research Council
View Funded Activity