Structure-Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and...

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Current chronic myeloid leukemia (CML) treatments targeting BCR-ABL1 kinase do not eradicate leukemic stem cells (LSCs).
• MNK1 and MNK2 inhibitors show potential by inhibiting eIF4E phosphorylation and LSC self-renewal.

Purpose of the Study:

• To identify novel dual inhibitors targeting both MNK1/2 and BCR-ABL1.
• To develop orally bioavailable compounds with improved efficacy against LSCs.

Main Methods:

• Structure-activity relationship (SAR) studies were performed starting from a known kinase inhibitor.
• In vitro kinase inhibition assays and in vivo efficacy studies in a mouse xenograft model were conducted.
• Analysis of phosphorylated eukaryotic translation initiation factor 4E (p-eIF4E) levels in tumor tissues.

Main Results:

• Compound 27 showed initial promise but lost BCR-ABL1 inhibition.
• Orally bioavailable dual MNK1/2 and BCR-ABL1 inhibitors, compounds 53 and 54, were identified.
• Compounds 53 and 54 demonstrated efficacy in a mouse xenograft model and reduced p-eIF4E levels.

Conclusions:

• Novel dual MNK1/2 and BCR-ABL1 inhibitors were successfully developed.
• These compounds represent a promising therapeutic strategy for targeting LSCs in CML.
• Further investigation into kinase selectivity and therapeutic potential is warranted.