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Cited by 63Chronic Lymphocytic Leukemia ResearchProtein Degradation and InhibitorsLymphoma Diagnosis and Treatment

BTK inhibitors: past, present, and future

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Cool, Allison, Nong, Tiffany, Montoya, Skye, Taylor, Justin·2024·Trends in Pharmacological Sciences
DOI 10.1016/j.tips.2024.06.006PMC PMC11864106
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Abstract

Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment landscape for B cell lymphomas such as chronic lymphocytic leukemia (CLL). The first-in-class BTK inhibitor ibrutinib has recently been succeeded by covalent BTK inhibitors that are safer but still face challenges of resistance mutations. The noncovalent BTK inhibitor pirtobrutinib was recently approved for relapsed and refractory CLL, and whether noncovalent BTK inhibitors will supplant covalent BTK inhibitors as upfront treatment options either alone or in combination will be determined. Meanwhile, newer BTK inhibitors and BTK degraders are vying for their place in the potential future landscape of B cell cancers as well as autoimmune diseases. This review will cover the latest progress in BTK inhibitor development and where the field is moving in light of these recent discoveries.

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  • Additional missense mutations of C481 have been identified which make the BTK-ibrutinib bond reversible and unstable, including C481A, C481R, C481F, and C481Y, among others at C481 which are less common.

    “Subsequently, additional missense mutations of C481 have been identified which make the BTK-ibrutinib bond reversible and unstable, including C481A, C481R, C481F, and C481Y, among others at C481 which are less common (12, 24, 36).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [36]

    The “Covalent BTK Inhibitors” section (page unavailable) says that acquired C481 mutations can cause resistance to covalent inhibitors, including ibrutinib. It does not identify C481A, C481R, C481F, or C481Y, establish that they are less common, or describe an unstable, reversible BTK–ibrutinib bond; the paper’s discussion of reversible inhibition concerns noncovalent inhibitors. (LLM, conf=0.86)

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Authors
Cool, A., Nong, T., Montoya, S., & Taylor, J.
Affiliations
University of Miami (US)
Corresponding author
Taylor, Justin
ORCID
Venue
Trends in Pharmacological Sciences
Publisher
Elsevier BV
Published
2024-08
Volume
45
Issue
8
Pages
691-707
ISSN
0165-6147 (ISSN-L)
DOI
10.1016/j.tips.2024.06.006
PMC
PMC11864106
OpenAlex
W4400736234
Cited by
63
References
7
Citations by year
2026: 36 · 2025: 26 · 2024: 1
FWCI
4.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Pharmacological Sciences (acceptedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute
  • National Institute of General Medical Sciences (R35GM151109)
  • National Institutes of Health
  • Doris Duke Charitable Foundation
  • Edward P Evans Foundation
  • Sylvester Comprehensive Cancer Center, University of Miami Health Systems (P30CA240139)
Topics
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
Keywords
BTK inhibitors, ibrutinib, pirtobrutinib, chronic lymphocytic leukemia, B-cell lymphoma, covalent BTK inhibitors, BTK degraders, resistance mutations, autoimmune disease
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Animals, Antineoplastic Agents, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Protein Kinase Inhibitors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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