Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Autor(en): | Nair, Pramod C. Piehler, Jacob Tvorogov, Denis Ross, David M. Lopez, Angel F. Gotlib, Jason Thomas, Daniel |
Stichwörter: | Drug Discovery; Humans; Janus Kinase 2; Janus Kinase Inhibitors; Mutation; Myeloproliferative Disorders; Neoplasms; deucravacitinib; fedratinib; Janus kinase 2 inhibitor; pacritinib; ruxolitinib; JAK2 protein, human; Janus kinase 2; Janus kinase inhibitor; antineoplastic activity; drug design; drug structure; high throughput screening; human; JAK-STAT signaling; kinase assay; myeloproliferative neoplasm; Review; drug development; genetics; mutation; myeloproliferative disorder; neoplasm | Erscheinungsdatum: | 2023 | Herausgeber: | American Association for Cancer Research Inc. | Journal: | Blood Cancer Discovery | Volumen: | 4 | Ausgabe: | 5 | Startseite: | 352 – 364 | Zusammenfassung: | 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. © 2023 American Association for Cancer Research. |
Beschreibung: | Cited by: 0; All Open Access, Green Open Access |
ISSN: | 2643-3230 | DOI: | 10.1158/2643-3230.BCD-22-0189 | Externe URL: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85169502726&doi=10.1158%2f2643-3230.BCD-22-0189&partnerID=40&md5=c3722184c96209b22a04f33ef60b0dec |
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