What question did this study set out to answer?

This research aims to develop terpene analogues of imatinib and evaluate their impact on BCR-ABL signaling in leukemia.

January 25, 2026Open Access

Rational Design, Synthesis, and Molecular Docking of Novel Terpene Analogues of Imatinib, and Their Inhibition on Downstream BCR-ABL Signaling

Key Points

This research aims to develop terpene analogues of imatinib and evaluate their impact on BCR-ABL signaling in leukemia.
Designed and synthesized nine imatinib analogues with bulky aliphatic moieties.
Characterized compounds using NMR spectroscopy and high-resolution mass spectrometry.
Conducted molecular docking to study binding modes and interactions.
Evaluated cytotoxicity in BCR-ABL+ leukemia cell lines using MTT assays.
Performed proteome-wide phosphokinase profiling to analyze signaling pathways.
Molecular docking revealed conserved interactions within the ATP-binding site of BCR-ABL for all derivatives.
Cytotoxicity assays showed improved antiproliferative activity of the analogues compared to imatinib.
Compound 6a exhibited IC50 of 1.1 μM and 6d had IC50 of 1.2 μM in the AR-230 model.
Both compounds preferentially suppressed different downstream signaling pathways, influencing cell survival and apoptotic responses.

Abstract

Background/Objectives: Imatinib, the first tyrosine kinase inhibitor, marks the beginning of a revolution in clinical oncology. Disrupting oncogenic kinase-dependent signaling pathways represents a key strategy for advancing targeted cancer therapies. Terpene analogues of imatinib were developed to probe the influence of terminal ring modifications on BCR-ABL inhibition and downstream oncogenic signaling. Methods: Nine novel imatinib analogues bearing bulky aliphatic moieties were designed, synthesised, and structurally characterized by 1H/13C NMR spectroscopy and high-resolution mass spectrometry (HRMS). Molecular docking calculations were performed to assess the binding modes and intermolecular interactions. The cytotoxicity of the newly synthesized imatinib derivatives was evaluated across a panel of BCR-ABL+ leukemia cell lines. Results: Molecular docking analyses demonstrated conserved interactions within the ATP-binding site of BCR-ABL for all derivatives, with calculated docking scores ranging between 123 and 128, while modifications at the terminal ring introduced subtle changes in electrostatic and steric profiles. Biological evaluation using MTT-based cytotoxicity assays in BCR-ABL+ leukemic cell lines revealed enhanced antiproliferative activity compared with imatinib, with compounds 6a (flexible cyclohexyl) and 6d (rigid camphane-type (+)-isopinocampheyl) exhibiting the lowest micromolar activity in the AR-230 model (IC50 values of 1.1 and 1.2 μM, respectively). Proteome-wide phosphokinase profiling demonstrated shared suppression of STAT5/3/6, RSK1/2, S6K1/p70, and Pyk2, confirming effective disruption of canonical BCR-ABL pathways. Critically, the terpene moiety dictated downstream pathway bias: 6a preferentially attenuated CREB activation, whereas 6d more effectively suppressed the PI3K/Akt oncogenic axis and strongly activated proapoptotic p53-mediated stress responses. Conclusions: Our findings establish terpene-engineered imatinib analogues as tunable modulators and promising candidates for targeting downstream BCR-ABL signaling pathways in leukemia treatment.

Rational Design, Synthesis, and Molecular Docking of Novel Terpene Analogues of Imatinib, and Their Inhibition on Downstream BCR-ABL Signaling

Key Points

Abstract

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