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BTK gatekeeper resi...
BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib
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- Estupinan, HY (author)
- Karolinska Institute,Karolinska Institutet,Universidad Industrial de Santander,Karolinska University Hospital
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- Wang, Q (author)
- Karolinska Institute,Karolinska Institutet,Karolinska University Hospital
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- Berglof, A (author)
- Karolinska Institute,Karolinska University Hospital
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- Schaafsma, Gerard C.P. (author)
- Lund University,Lunds universitet,Proteinbioinformatik,Forskargrupper vid Lunds universitet,Protein Bioinformatics,Lund University Research Groups
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- Shi, YY (author)
- Huaian First People's Hospital,Nanjing Medical University
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- Zhou, LT (author)
- Huaian First People's Hospital,Nanjing Medical University
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- Mohammad, DK (author)
- Karolinska Institute,Karolinska Institutet,Salahaddin University
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- Yu, L (author)
- Huaian First People's Hospital,Nanjing Medical University
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- Vihinen, Mauno (author)
- Lund University,Lunds universitet,Proteinbioinformatik,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Protein Bioinformatics,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Zain, R (author)
- Karolinska Institute,Karolinska Institutet,Karolinska University Hospital
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- Smith, CIE (author)
- Karolinska Institute,Karolinska Institutet,Karolinska University Hospital
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(creator_code:org_t)
- 2021-02-01
- 2021
- English.
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In: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 35:85, s. 1317-1329
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Abstract
Subject headings
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- Irreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the “gatekeeper” residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants were subsequently combined with replacement of the cysteine 481 residue to which irreversible inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, bind. We found that certain double mutants, such as threonine 474 to isoleucine (T474I) or methionine (T474M) combined with catalytically active cysteine 481 to serine (C481S), are insensitive to ≥16-fold the pharmacological serum concentration, and therefore defined as super-resistant to irreversible inhibitors. Conversely, reversible inhibitors showed a variable pattern, from resistance to no resistance, collectively demonstrating the structural constraints for different classes of inhibitors, which may affect their clinical application.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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Leukemia
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To the university's database
- By the author/editor
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Estupinan, HY
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Wang, Q
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Berglof, A
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Schaafsma, Gerar ...
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Shi, YY
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Zhou, LT
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show more...
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Mohammad, DK
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Yu, L
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Vihinen, Mauno
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Zain, R
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Smith, CIE
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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Leukemia
- By the university
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Karolinska Institutet
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Lund University