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From development to clinical success: the journey of established and next-generation BTK inhibitors

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Summary

Over the past decade, Bruton’s tyrosine kinase (BTK) has emerged as a pivotal therapeutic target for B-cell malignancies and autoimmune diseases, given its essential role in B-cell development and function. Dysregulation of BTK signalling is implicated in a range of hematologic cancers, including Waldenström’s macroglobulinaemia (WM), mantle cell lymphoma (MCL), and chronic lymphocytic leukaemia (CLL). The development of BTK inhibitors (BTKIs), starting with ibrutinib, has revolutionized the treatment of these malignancies by inhibiting B-cell receptor (BCR) signalling and inducing apoptosis in malignant B-cells. Despite the impressive clinical efficacy of ibrutinib, challenges such as resistance mutations and off-target effects remain. To address these issues, next-generation BTKIs, including acalabrutinib, orelabrutinib, zanubrutinib, and pirtobrutinib, have been developed, offering improved specificity and reduced toxicity profiles. This review highlights the therapeutic potential of BTK-targeted therapies in treating B-cell malignancies, discusses recent advancements with FDA-approved BTKIs, and explores the latest clinical outcomes from ongoing trials of novel inhibitors.

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Acknowledgements

The authors would like to express their sincere gratitude to the Life Sciences Research Board (LSRB), Defence Research and Development Organisation (DRDO), Government of India, for their financial support throughout this research. The authors are also thankful to MoE, India, for providing PhD fellowship to author Arpit Sharma.

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  1. Biomolecular Engineering Laboratory, School of Biochemical Engineering, IIT (BHU), Varanasi, 221005, India

    Shivani Gupta, Arpit Sharma, Alok Shukla & Abha Mishra

  2. Department of Pharmacology, Institute of Medical Science, Banaras Hindu University, Varanasi, 221005, India

    Amit Singh

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Contributions

Shivani Gupta: writing—original draft, writing—review and editing, conceptualization and investigation

Arpit Sharma: writing—review and editing, investigation, conceptualization.

Alok Shukla: writing—review and editing, investigation, conceptualization.

Amit Singh: writing—review and editing, supervision, conceptualization, and investigation.

Abha Mishra: writing—review and editing, supervision, conceptualization, and investigation.

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Gupta, S., Sharma, A., Shukla, A. et al. From development to clinical success: the journey of established and next-generation BTK inhibitors. Invest New Drugs 43, 377–393 (2025). https://doi.org/10.1007/s10637-025-01513-y

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