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Published on: May 15, 2019
Effects of Pimozide Derivatives on pSTAT5 in K562 Cells
Riccardo Rondanin1, Daniele Simoni1, Martina Maccesi1
1Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, via Fossato di Mortara 17, 44121, Ferrara, Italy.
Abstract:
STAT5 is a transcription factor, a member of the STAT family of signaling proteins. STAT5 is involved in many types of cancer, including chronic myelogenous leukemia (CML), in which this protein is found constitutively activated as a consequence of BCR-ABL expression. The neuroleptic drug pimozide was recently reported to act as an inhibitor of STAT5 phosphorylation and is capable of inducing apoptosis in CML cells in vitro. Our research group has synthesized simple derivatives of pimozide with cytotoxic activity and that are able to decrease the levels of phosphorylated STAT5. In this work we continued the search for novel STAT5 inhibitors, synthesizing compounds in which the benzoimidazolinone ring of pimozide is either maintained or modified, in order to obtain further structure-activity relationship information for this class of STAT5 inhibitors. Two compounds of the series showed potent cytotoxic activity against BCR-ABL-positive and pSTAT5-overexpressing K562 cells and were able to markedly decrease the levels of phosphorylated STAT5.
Insights
Researchers synthesized novel pimozide derivatives to inhibit signal transducer and activator of transcription 5 (STAT5) phosphorylation. Two compounds demonstrated potent cytotoxic effects against chronic myelogenous leukemia (CML) cells by reducing STAT5 activity.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Signal transducer and activator of transcription 5 (STAT5) is a key protein implicated in various cancers, notably chronic myelogenous leukemia (CML).
- Constitutive activation of STAT5, often due to BCR-ABL expression in CML, drives cancer cell proliferation.
- The drug pimozide has shown potential as a STAT5 inhibitor, inducing apoptosis in CML cells.
Purpose of the Study:
- To synthesize and evaluate novel pimozide derivatives as STAT5 inhibitors.
- To explore structure-activity relationships for benzoimidazolinone-based STAT5 inhibitors.
- To identify compounds with potent cytotoxic activity against BCR-ABL-positive CML cells.
Main Methods:
- Synthesis of pimozide derivatives, modifying the benzoimidazolinone core.
- Assessment of cytotoxic activity against K562 cells (BCR-ABL-positive, pSTAT5-overexpressing).
- Measurement of phosphorylated STAT5 (pSTAT5) levels in treated cells.
Main Results:
- Two novel compounds exhibited significant cytotoxic effects on K562 cells.
- These compounds effectively reduced the levels of phosphorylated STAT5.
- The modifications to the benzoimidazolinone ring were crucial for activity.
Conclusions:
- Novel pimozide derivatives can act as effective STAT5 inhibitors.
- These compounds hold promise for the development of new CML therapies.
- Further structure-activity relationship studies can optimize STAT5 inhibition.
