Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches

Pramod C. Nair, Jacob Piehler, Denis Tvorogov, David M. Ross, Angel F. Lopez, Jason Gotlib, Daniel Thomas

Research output: Contribution to journalReview articlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)352-364
Number of pages13
JournalBlood Cancer Discovery
Volume4
Issue number5
DOIs
Publication statusPublished or Issued - Sept 2023
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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