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

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• The JAK2 V617F mutation drives myeloproliferative neoplasms (MPNs), necessitating targeted therapies.
• Current Janus kinase (JAK) 2 inhibitors manage symptoms but do not eradicate MPNs due to limited selectivity.
• Recent structural studies reveal non-kinase domains contributing to JAK2 V617F oncogenicity.

Purpose of the Study:

• To evaluate structure-based approaches for developing selective JAK2 inhibitors.
• To assess currently approved and investigational JAK2 inhibitors.
• To explore the potential of full-length JAK homodimeric structures for future drug design.

Main Methods:

• Review of structure-based drug discovery approaches for JAK2 inhibitors.
• Analysis of Type I, Type II, and pseudokinase inhibitors.
• Examination of recently elucidated full-length JAK homodimeric structures.

Main Results:

• Structure-based design has yielded approved Type I JAK2 inhibitors (fedratinib, pacritinib).
• Type II (BBT594, CHZ868) and pseudokinase (JNJ7706621) inhibitors are under development.
• Availability of full-length JAK homodimeric structures facilitates the design of superior inhibitors.

Conclusions:

• Understanding JAK2 structure beyond the kinase domain is crucial for targeting V617F oncogenicity.
• Computational and structure-based drug discovery, combined with full-length JAK dimer knowledge, offers a unique opportunity for developing better targeted therapies.
• Future development of superior, selective, and mutation-specific JAK2 inhibitors is foreseeable.