Structure of BTK kinase domain with the second-generation inhibitors acalabrutinib and tirabrutinib

Lin, David Y.; Andreotti, Amy H.

doi:10.1371/journal.pone.0290872

Title: Structure of BTK kinase domain with the second-generation inhibitors acalabrutinib and tirabrutinib

Journal Article · 31 August 2023 · PLoS ONE

DOI: https://doi.org/10.1371/journal.pone.0290872 · OSTI ID:2423656

^[1];

^[1]

Iowa State University, Ames, IA (United States)

Bruton’s tyrosine kinase (BTK) is the target of the therapeutic agent, Ibrutinib, that treats chronic lymphocyte leukemia (CLL), mantle cell lymphoma (MCL) and other B cell malignancies. Ibrutinib is a first in class, covalent BTK inhibitor that limits B-cell survival and proliferation. Designing new inhibitors of BTK has been an important objective for advancing development of improved therapeutic agents against cancer and autoimmune disorders. Based on the success of Ibrutinib, several second-generation irreversible BTK inhibitors have been developed that exhibit fewer off-target effects. However, the binding-mode and their interaction with Btk have not been experimentally determined and evaluated at atomic resolution. Here we determined the first crystal structure of the BTK kinase domain in complex with acalabrutinib. In addition, we report a structure of the BTK/tirabrutinib complex and compare these structures with previously solved structures. The structures provide insight in the superior selectivity reported for acalabrutinb and guide future BTK inhibitor development.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2423656

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 8 Vol. 18; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

References (48)

Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia Maddocks, Kami J.; Ruppert, Amy S.; Lozanski, Gerard JAMA Oncology, Vol. 1, Issue 1 https://doi.org/10.1001/jamaoncol.2014.218	journal	April 2015
Discovery of Selective Irreversible Inhibitors for Bruton’s Tyrosine Kinase Pan, Zhengying; Scheerens, Heleen; Li, Shyr-Jiann ChemMedChem, Vol. 2, Issue 1 https://doi.org/10.1002/cmdc.200600221	journal	January 2007
Targeting Bruton's tyrosine kinase with ibrutinib in B‐cell malignancies Wang, Y.; Zhang, Ll; Champlin, Re Clinical Pharmacology & Therapeutics, Vol. 97, Issue 5 https://doi.org/10.1002/cpt.85	journal	April 2015
Targeting BTK in CLL: Beyond Ibrutinib Bond, David A.; Woyach, Jennifer A. Current Hematologic Malignancy Reports, Vol. 14, Issue 3 https://doi.org/10.1007/s11899-019-00512-0	journal	April 2019
Zanubrutinib: First Approval Syed, Yahiya Y. Drugs, Vol. 80, Issue 1 https://doi.org/10.1007/s40265-019-01252-4	journal	January 2020
Tirabrutinib: First Approval Dhillon, Sohita Drugs, Vol. 80, Issue 8 https://doi.org/10.1007/s40265-020-01318-8	journal	May 2020
Orelabrutinib: First Approval Dhillon, Sohita Drugs, Vol. 81, Issue 4 https://doi.org/10.1007/s40265-021-01482-5	journal	March 2021
Tec family kinases in lymphocyte signaling and function Schaeffer, Edward M.; Schwartzberg, Pamela L. Current Opinion in Immunology, Vol. 12, Issue 3 https://doi.org/10.1016/S0952-7915(00)00088-1	journal	June 2000
The development of Bruton's tyrosine kinase (BTK) inhibitors from 2012 to 2017: A mini-review Liang, Chengyuan; Tian, Danni; Ren, Xiaodong European Journal of Medicinal Chemistry, Vol. 151 https://doi.org/10.1016/j.ejmech.2018.03.062	journal	May 2018
Emerging small-molecule inhibitors of the Bruton’s tyrosine kinase (BTK): Current development Liu, Jiakuo; Chen, Chengjuan; Wang, Dongmei European Journal of Medicinal Chemistry, Vol. 217 https://doi.org/10.1016/j.ejmech.2021.113329	journal	May 2021
Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase Guo, Yunhang; Liu, Ye; Hu, Nan Journal of Medicinal Chemistry, Vol. 62, Issue 17 https://doi.org/10.1021/acs.jmedchem.9b00687	journal	August 2019
The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases Vetrie, David; Vořechovský, Igor; Sideras, Paschalis Nature, Vol. 361, Issue 6409 https://doi.org/10.1038/361226a0	journal	January 1993
Functional characterization of BTKC481S mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors Cheng, S.; Guo, A.; Lu, P. Leukemia, Vol. 29, Issue 4 https://doi.org/10.1038/leu.2014.263	journal	September 2014
Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances Wen, Tingyu; Wang, Jinsong; Shi, Yuankai Leukemia, Vol. 35, Issue 2 https://doi.org/10.1038/s41375-020-01072-6	journal	October 2020
Ibrutinib Resistance in Chronic Lymphocytic Leukemia Furman, Richard R.; Cheng, Shuhua; Lu, Pin New England Journal of Medicine, Vol. 370, Issue 24 https://doi.org/10.1056/NEJMc1402716	journal	June 2014
Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib Woyach, Jennifer A.; Furman, Richard R.; Liu, Ta-Ming New England Journal of Medicine, Vol. 370, Issue 24 https://doi.org/10.1056/NEJMoa1400029	journal	June 2014
Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia Byrd, John C.; Harrington, Bonnie; O’Brien, Susan New England Journal of Medicine, Vol. 374, Issue 4 https://doi.org/10.1056/NEJMoa1509981	journal	January 2016
The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy Honigberg, L. A.; Smith, A. M.; Sirisawad, M. Proceedings of the National Academy of Sciences, Vol. 107, Issue 29 https://doi.org/10.1073/pnas.1004594107	journal	July 2010
Bruton’s tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010-2018) Feng, Yifan; Duan, Weiming; Cu, Xiaochuan Expert Opinion on Therapeutic Patents, Vol. 29, Issue 4 https://doi.org/10.1080/13543776.2019.1594777	journal	March 2019
Approved and emerging Bruton’s tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia Hatashima, Alycia; Karami, Mehdi; Shadman, Mazyar Expert Opinion on Pharmacotherapy, Vol. 23, Issue 13 https://doi.org/10.1080/14656566.2022.2113384	journal	August 2022
Beyond ibrutinib: novel BTK inhibitors for the treatment of chronic lymphocytic leukemia Perutelli, Francesca; Montalbano, Maria Chiara; Boccellato, Elia Current Opinion in Oncology, Vol. 34, Issue 6 https://doi.org/10.1097/CCO.0000000000000897	journal	August 2022
Bruton Tyrosine Kinase Inhibitors Burger, Jan A. The Cancer Journal, Vol. 25, Issue 6 https://doi.org/10.1097/PPO.0000000000000412	journal	November 2019
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
electronic Ligand Builder and Optimization Workbench ( eLBOW ): a tool for ligand coordinate and restraint generation Moriarty, Nigel W.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 10 https://doi.org/10.1107/S0907444909029436	journal	September 2009
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
Data processing and analysis with the autoPROC toolbox Vonrhein, Clemens; Flensburg, Claus; Keller, Peter Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444911007773	journal	March 2011
JLigand : a graphical tool for the CCP 4 template-restraint library Lebedev, Andrey A.; Young, Paul; Isupov, Michail N. Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/S090744491200251X	journal	March 2012
How good are my data and what is the resolution? Evans, Philip R.; Murshudov, Garib N. Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7 https://doi.org/10.1107/S0907444913000061	journal	June 2013
Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix Liebschner, Dorothee; Afonine, Pavel V.; Baker, Matthew L. Acta Crystallographica Section D Structural Biology, Vol. 75, Issue 10 https://doi.org/10.1107/S2059798319011471	journal	October 2019
Bruton's tyrosine kinase inhibition—An emerging therapeutic strategy in immune‐mediated dermatological conditions Mendes‐Bastos, Pedro; Brasileiro, Ana; Kolkhir, Pavel Allergy, Vol. 77, Issue 8 https://doi.org/10.1111/all.15261	journal	February 2022
Comparison of ibrutinib and idelalisib plus rituximab in real‐life relapsed/resistant chronic lymphocytic leukemia cases Morabito, Fortunato; Tripepi, Giovanni; Del Poeta, Giovanni European Journal of Haematology, Vol. 106, Issue 4 https://doi.org/10.1111/ejh.13573	journal	January 2021
Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile Barf, Tjeerd; Covey, Todd; Izumi, Raquel Journal of Pharmacology and Experimental Therapeutics, Vol. 363, Issue 2 https://doi.org/10.1124/jpet.117.242909	journal	September 2017
Ability of Bruton’s Tyrosine Kinase Inhibitors to Sequester Y551 and Prevent Phosphorylation Determines Potency for Inhibition of Fc Receptor but not B-Cell Receptor Signaling Bender, Andrew T.; Gardberg, Anna; Pereira, Albertina Molecular Pharmacology, Vol. 91, Issue 3 https://doi.org/10.1124/mol.116.107037	journal	January 2017
Activation Loop Dynamics Determine the Different Catalytic Efficiencies of B Cell- and T Cell-Specific Tec Kinases Joseph, R. E.; Kleino, I.; Wales, T. E. Science Signaling, Vol. 6, Issue 290 https://doi.org/10.1126/scisignal.2004298	journal	August 2013
The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia Herman, Sarah E. M.; Montraveta, Arnau; Niemann, Carsten U. Clinical Cancer Research, Vol. 23, Issue 11 https://doi.org/10.1158/1078-0432.CCR-16-0463	journal	May 2017
Comparison of Acalabrutinib, A Selective Bruton Tyrosine Kinase Inhibitor, with Ibrutinib in Chronic Lymphocytic Leukemia Cells Patel, Viralkumar; Balakrishnan, Kumudha; Bibikova, Elena Clinical Cancer Research, Vol. 23, Issue 14 https://doi.org/10.1158/1078-0432.CCR-16-1446	journal	July 2017
The potential of pirtobrutinib in multiple B-cell malignancies Jensen, Jeffrey L.; Mato, Anthony R.; Pena, Camila Therapeutic Advances in Hematology, Vol. 13 https://doi.org/10.1177/20406207221101697	journal	January 2022
Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation Liu, Ta-Ming; Woyach, Jennifer A.; Zhong, Yiming Blood, Vol. 126, Issue 1 https://doi.org/10.1182/blood-2015-02-626846	journal	July 2015
Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia Burger, Jan A.; Sivina, Mariela; Jain, Nitin Blood, Vol. 133, Issue 10 https://doi.org/10.1182/blood-2018-10-879429	journal	March 2019
Potency and Selectivity of BTK Inhibitors in Clinical Development for B-Cell Malignancies Kaptein, Allard; de Bruin, Gerjan; Emmelot-van Hoek, Maaike Blood, Vol. 132, Issue Supplement 1 https://doi.org/10.1182/blood-2018-99-109973	journal	November 2018
BTK^C481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia Woyach, Jennifer A.; Ruppert, Amy S.; Guinn, Daphne Journal of Clinical Oncology, Vol. 35, Issue 13 https://doi.org/10.1200/JCO.2016.70.2282	journal	May 2017
Bruton’s Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures Ringheim, Garth E.; Wampole, Matthew; Oberoi, Kinsi Frontiers in Immunology, Vol. 12 https://doi.org/10.3389/fimmu.2021.662223	journal	November 2021
Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective Brullo, Chiara; Villa, Carla; Tasso, Bruno International Journal of Molecular Sciences, Vol. 22, Issue 14 https://doi.org/10.3390/ijms22147641	journal	July 2021
Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases Zhang, Datong; Gong, He; Meng, Fancui Molecules, Vol. 26, Issue 16 https://doi.org/10.3390/molecules26164907	journal	August 2021
Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate Wang, Qi; Vogan, Erik M.; Nocka, Laura M. eLife, Vol. 4 https://doi.org/10.7554/eLife.06074	journal	February 2015
Differential impact of BTK active site inhibitors on the conformational state of full-length BTK Joseph, Raji E.; Amatya, Neha; Fulton, D. Bruce eLife, Vol. 9 https://doi.org/10.7554/eLife.60470	journal	November 2020

Similar Records

Battling Btk Mutants With Noncovalent Inhibitors That Overcome Cys481 and Thr474 Mutations

Journal Article · 2016 · ACS Chemical Biology · OSTI ID:1347790

Johnson, Adam R.; Kohli, Pawan Bir; Katewa, Arna; +19 more

Design and synthesis of carbazole carboxamides as promising inhibitors of Bruton’s tyrosine kinase (BTK) and Janus kinase 2 (JAK2)

Journal Article · 2015 · Bioorganic & Medicinal Chemistry Letters · OSTI ID:1347758

Liu, Qingjie; Batt, Douglas G.; Lippy, Jonathan S.; +12 more

Discovery of 8-Amino-imidazo[1,5- a ]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis

Journal Article · 2015 · ACS Medicinal Chemistry Letters · OSTI ID:1404965

Liu, Jian; Guiadeen, Deodial; Krikorian, Arto; +31 more

Related Subjects

60 APPLIED LIFE SCIENCES
B cells
Cancer treatment
Crystal structure
Crystallization
Crystals
Drug interactions
Molecular structure
Science & Technology
Tyrosine kinases

Title: Structure of BTK kinase domain with the second-generation inhibitors acalabrutinib and tirabrutinib

Citation Formats

References (48)

Similar Records

Related Subjects