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Updated: May 28, 2026
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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
A46, a benzothiophene-derived compound, suppresses Jak2-mediated pathologic cell growth
Anurima Majumder1, Andrew T Magis, Sung O Park
1Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Experimental Hematology
|October 25, 2011
Summary
A novel benzothiophene compound, A46, effectively inhibits the Janus kinase 2 (Jak2) V617F mutation. This Jak2 inhibitor shows therapeutic potential for myeloproliferative neoplasms by reducing cancer cell growth and disease progression in vivo.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Hyperactive Janus kinase 2 (Jak2) tyrosine kinase signaling is a hallmark of myeloproliferative neoplasms (MPNs).
- Targeting Jak2 offers a promising therapeutic strategy for hematological malignancies.
Purpose of the Study:
- To identify and characterize a novel benzothiophene-derived inhibitor, A46, targeting the Jak2 V617F mutation.
- To evaluate the efficacy of A46 in preclinical models of Jak2-driven MPNs.
Main Methods:
- Structure-based virtual screening to identify A46.
- In vitro enzymatic assays to assess Jak2 inhibition.
- Cell-based assays using Jak2-V617F-expressing cell lines and primary human bone marrow cells.
- In vivo studies using a mouse model of Jak2-V617F-mediated MPN.
Main Results:
- A46 selectively inhibited Jak2-V617F protein activity.
- A46 suppressed proliferation of Jak2-V617F-expressing cells, inducing cell cycle arrest and apoptosis.
- A46 reduced aberrant growth of primary human bone marrow cells ex vivo.
- In vivo, A46 significantly ameliorated splenomegaly, megakaryocytic hyperplasia, and reduced IL-6 levels in a Jak2-V617F mouse model.
Conclusions:
- The benzothiophene derivative A46 demonstrates potent and selective inhibition of Jak2-V617F.
- A46 exhibits preclinical efficacy against Jak2-mediated MPNs, highlighting its potential as a therapeutic agent.
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