Small Molecule Inhibitors of Pleckstrin-2 for Treating Myeloproliferative Neoplasms

SHORT DESCRIPTION
Small molecule inhibitors of Pleckstrin-2 (Plek2) for treating cell proliferative diseases and disorders, particularly myeloproliferative neoplasms (MPNs).

NU Tech IDs: NU 2018-169, NU 2021-005

PRINCIPAL INVESTIGATOR

• Peng Ji
  • Northwestern University Feinberg School of Medicine, Department of Pathology

IP STATUS

Multiple US patents pending (17/309,179,  18/260,373)

DEVELOPMENT STAGE

TRL-4 Prototype Validated in Lab: In vitro and in vivo studies confirm key functions of the inhibitors.

BACKGROUND

Myeloproliferative neoplasms (MPNs) are bone marrow diseases characterized by the excessive production of myeloid cells and increased risk of evolving to acute myeloid leukemia (AML). The JAK2-V617F mutation is the leading cause of Philadelphia chromosome (Ph)-negative MPNs, and while JAK2 inhibitors have been developed, they face challenges including drug resistance and severe side effects. The inventors discovered Pleckstrin-2 (Plek2) as a novel target downstream of the JAK2/STAT5 pathway that works to enhance the activity of Akt through the recruitment of downstream effector proteins. Plek2 is highly expressed in MPNs and represents a promising new therapeutic target.

ABSTRACT
Northwestern researchers have developed small molecule inhibitors of Plek2 for treating MPNs and other cancers linked to high Plek2 expression. First-generation indole-based compounds were optimized through rational medicinal chemistry to generate second-generation quinoline-based inhibitors with enhanced Plek2 specificity. In vitro, the inhibitors effectively block proliferation of hematopoietic cells  from mice and humans at levels comparable to FDA-approved JAK2 inhibitors. In vivo, the inhibitors reduce thrombosis formation and demonstrate therapeutic efficacy similar to genetic depletion of Plek2. The compounds may be conjugated to E3 ligase recruiters via linkers to form proteolysis-targeting chimeric molecules (PROTACs). These novel Plek2 inhibitors have broad therapeutic application in MPNs, as well as cancers with high Plek2 expression, especially those that are characterized by activation of the PI3K-Akt pathway.

APPLICATIONS

• Treatment of Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs)
• Treatment of other diseases and disorders characterized by high Plek2 expression or activation of the phosphatidylinositide 3-kinase (PI3K)/Akt pathway
• Synergistic treatment with other therapies such as with Akt inhibitors for enhanced efficacies
• Development of novel PROTACs to induce degradation of Plek2
• Use as a research tool to study Plek2 and PI3K signaling pathways

ADVANTAGES

• First-in-class compounds with novel targeting mechanisms through JAK2-STAT5 effector and PI3K-Akt activation
• Superior therapeutic profile compared to current MPN drugs, indicating Plek2's disease-specific role and suggesting reduced side effects
• Broad therapeutic applications not only in MPN, but also other cancers with high Plek2 expression and/or activation of PI3K-Akt
• Protein degradation capability via conjugation to E3 ligase recruiters

PUBLICATIONS

• Zhao et al., Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2-V617F-positive myeloproliferative neoplasms, J Clin Invest, Nov 20, 2017
• Han et al., Targeting pleckstrin-2/Akt signaling reduces proliferation in myeloproliferative neoplasm models, J Clin Invest, Mar 15, 2023

CATEGORY/INDUSTRY PIPELINE

• Therapeutics
• Biomarkers & Biomedical Research Tools

KEYWORDS

Oncology, cancer, myeloproliferative neoplasms, leukemia, small molecule, inhibitor, hematology, Plek2 inhibitors, blood disease therapy, thrombosis reduction