Battling Btk mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations
Abstract
The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has shown impressive clinical efficacy in a range of B-cell malignancies. However, acquired resistance has emerged, and second generation therapies are now being sought. Ibrutinib is a covalent, irreversible inhibitor that modifies Cys481 in the ATP binding site of Btk and renders the enzyme inactive, thereby blocking B-cell receptor signal transduction. Not surprisingly, Cys481 is the most commonly mutated Btk residue in cases of acquired resistance to ibrutinib. Mutations at other sites, including Thr474, a gatekeeper residue, have also been detected. Herein, we describe noncovalent Btk inhibitors that differ from covalent inhibitors like ibrutinib in that they do not interact with Cys481, they potently inhibit the ibrutinib-resistant Btk C481S mutant in vitro and in cells, and they are exquisitely selective for Btk. Noncovalent inhibitors such as GNE-431 also show excellent potency against the C481R, T474I, and T474M mutants. X-ray crystallographic analysis of Btk provides insight into the unique mode of binding of these inhibitors that explains their high selectivity for Btk and their retained activity against mutant forms of Btk. This class of noncovalent Btk inhibitors may provide a treatment option to patients, especially those who have acquired resistance to ibrutinib by mutation of Cys481 or Thr474.
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New-generation noncovalent BTK inhibitors retain activity against Cys481 and gatekeeper Thr474 point mutants.
“Newgeneration noncovalent BTK inhibitors have been developed that retain activity against the Cys481 and gatekeeper Thr474 point mutants.34”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [34]
Many noncovalent BTK inhibitors have activity on WT and C481-mutant BTK with equal potency, and some consistently inhibit all mutants.
“Many of these noncovalent inhibitors have activity on WT and C481-mutant BTK with equal potency, and some even consistently inhibit all mutants.”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [34]
Cites
<i>EGFR</i> Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib
Kobayashi, S., Boggon, T. J., Dayaram, T., Jänne, P. A., Kocher, O., Meyerson, M., Johnson, B. E., Eck, M. J., Tenen, D. G., & Halmos, B. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa044238 · Cited by 3,964 · see citing works
Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia
Byrd, J. C., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., Grant, B., Sharman, J. P., Coleman, M., Wierda, W. G., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1215637 · Cited by 2,270 · see citing works
Self-citationThe resurgence of covalent drugs
Singh, J., Petter, R. C., Baillie, T. A., & Whitty, A. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3410 · Cited by 1,873 · see citing works
Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor
Shah, N. P., Tran, C., Lee, F. Y., Chen, P., Norris, D. J., & Sawyers, C. L. (2004) · Science · doi:10.1126/science.1099480 · Cited by 1,785 · see citing works
Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma
Wang, M. L., Rule, S., Martin, P., Goy, A., Auer, R., Kahl, B. S., Jurczak, W., Advani, R. H., Romaguera, J. E., Williams, M. E., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1306220 · Cited by 1,685 · see citing works
Shah, N. P., Nicoll, J. M., Nagar, B., Gorre, M. E., PAQUETTE, R. L., Kuriyan, J., & Sawyers, C. L. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00096-x · Cited by 1,608 · see citing works
Honigberg, L. A., Smith, A. M., Sirisawad, M., Verner, E., Loury, D., Chang, B., Li, S., Pan, Z., Thamm, D. H., Miller, R. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004594107 · Cited by 1,561 · see citing works
Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib
Woyach, J. A., Furman, R. R., Liu, T.-M., Ozer, H. G., Zapatka, M., Ruppert, A. S., Xue, L., Li, D. H.-H., Steggerda, S. M., Versele, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1400029 · Cited by 1,275 · see citing works
Self-citationAdvani, R. H., Buggy, J. J., Sharman, J. P., Smith, S. M., Boyd, T. E., Grant, B., Kolibaba, K. S., Furman, R. R., Rodriguez, S., Chang, B. Y., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.42.7906 · Cited by 1,128 · see citing works
Ibrutinib in Previously Treated Waldenström’s Macroglobulinemia
Treon, S. P., Tripsas, C. K., Meid, K., Warren, D. L., Varma, G., Green, R., Argyropoulos, K. V., Yang, G., Cao, Y., Xu, L., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1501548 · Cited by 939 · see citing works
Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia
Byrd, J. C., Harrington, B. K., O'Brien, S. M., Jones, J. A., Schuh, A., Devereux, S., Chaves, J. M., Wierda, W. G., Awan, F. T., Brown, J. R., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1509981 · Cited by 902 · see citing works
Self-citationDiscovery of Selective Irreversible Inhibitors for Bruton’s Tyrosine Kinase
Pan, Z., Scheerens, H., Li, S., Schultz, B. E., Sprengeler, P. A., Burrill, L. C., Mendonca, R. V., Sweeney, M. D., Scott, K. C. K., Grothaus, P. G., et al. (2006) · ChemMedChem · doi:10.1002/cmdc.200600221 · Cited by 690 · see citing works
Maddocks, K. J., Ruppert, A. S., Lozanski, G., Heerema, N. A., Zhao, W., Abruzzo, L., Lozanski, A., Davis, M., Gordon, A., Smith, L. L., et al. (2015) · JAMA Oncology · doi:10.1001/jamaoncol.2014.218 · Cited by 584 · see citing works
Self-citationProlonged and tunable residence time using reversible covalent kinase inhibitors
Bradshaw, J. M., McFarland, J. M., Paavilainen, V. O., Bisconte, A. R., Tam, D., Phan, V. T., Romanov, S., Finkle, D., Shu, J., Patel, V. P., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1817 · Cited by 428 · see citing works
McMullen, J. R., Boey, E. J. H., Ooi, J. Y. Y., Seymour, J. F., Keating, M. J., & Tam, C. S. L. (2014) · Blood · doi:10.1182/blood-2014-10-604272 · Cited by 407 · see citing works
Self-citationA road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors
Lanning, B. R., Whitby, L. R., Dix, M. M., Douhan, J., Gilbert, A. M., Hett, E. C., Johnson, T., Joslyn, C. M., Kath, J. C., Niessen, S., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1582 · Cited by 356 · see citing works
Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis
Di Paolo, J. A., Huang, T., Balazs, M., Barbosa, J., Barck, K. H., Bravo, B. J., Carano, R. A. D., Darrow, J., Davies, D. R., DeForge, L. E., et al. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.481 · Cited by 340 · see citing works
Self-citationLynch, T. J., Kim, E. S., Eaby, B., Garey, J. S., West, D. P., & Lacouture, M. E. (2007) · The Oncologist · doi:10.1634/theoncologist.12-5-610 · Cited by 340 · see citing works
Ibrutinib Resistance in Chronic Lymphocytic Leukemia
Furman, R. R., Cheng, S., Lu, P., Setty, M., Perez, A. R., Guo, A., Racchumi, J., Xu, G., Wu, H., Ma, J., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmc1402716 · Cited by 300 · see citing works
Postibrutinib outcomes in patients with mantle cell lymphoma
Martin, P., Maddocks, K. J., Leonard, J. P., Ruan, J., Goy, A. H., Wagner‐Johnston, N. D., Rule, S. A., Advani, R. H., Iberri, D. J., Phillips, T. J., et al. (2016) · Blood · doi:10.1182/blood-2015-10-673145 · Cited by 298 · see citing works
Schwartz, P. A., Kuzmic, P., Solowiej, J., Bergqvist, S., Bolanos, B., Almaden, C., Nagata, A., Ryan, K., Feng, J., Dalvie, D., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1313733111 · Cited by 281 · see citing works
Walter, H. S., Rule, S. A., Dyer, M. J. S., Karlin, L., Jones, C. H., Cazin, B., Quittet, P., Shah, N., Hutchinson, C. V., Honda, H., et al. (2015) · Blood · doi:10.1182/blood-2015-08-664086 · Cited by 270 · see citing works
Evans, E. K., Tester, R. W., Aslanian, S., Karp, R., Sheets, M. P., Labenski, M., Witowski, S. R., Lounsbury, H. A., Chaturvedi, P., Mazdiyasni, H., et al. (2013) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.203489 · Cited by 223 · see citing works
Cheng, S.-H., Ma, J., Guo, A., Lu, P., Leonard, J., Coleman, M., Liu, M., Buggy, J., Furman, R., & Wang, Y.-L. (2014) · Leukemia · doi:10.1038/leu.2013.358 · Cited by 179 · see citing works
Cheah, C. Y., Chihara, D., Romaguera, J. E., Fowler, N. H., Seymour, J. F., Hagemeister, F. B., Champlin, R. E., & Wang, M. L. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv111 · Cited by 179 · see citing works
Liu, T.-M., Woyach, J. A., Zhong, Y., Lozanski, A., Lozanski, G., Dong, S., Strattan, E., Lehman, A., Zhang, X., Jones, J. A., et al. (2015) · Blood · doi:10.1182/blood-2015-02-626846 · Cited by 178 · see citing works
Self-citationMarcotte, D. J., Liu, Y., Arduini, R. M., Hession, C. A., Miatkowski, K., Wildes, C. P., Cullen, P. F., Hong, V. S., Hopkins, B. T., Mertsching, E., et al. (2010) · Protein Science · doi:10.1002/pro.321 · Cited by 158 · see citing works
Cheng, S.-H., Guo, A., Lu, P., Ma, J., Coleman, M., & Wang, Y.-L. (2014) · Leukemia · doi:10.1038/leu.2014.263 · Cited by 155 · see citing works
Xu, D., Kim, Y. D., Postelnek, J., Vu, M. D., Hu, D., Liao, C., Bradshaw, M., Hsu, J., Zhang, J., Pashine, A., et al. (2012) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.187740 · Cited by 142 · see citing works
Clinical Efficacy and Toxicity of Anti-EGFR Therapy in Common Cancers
Harandi, A., Zaidi, A., Stocker, A. M., & Laber, D. A. (2009) · Journal of Oncology · doi:10.1155/2009/567486 · Cited by 114 · see citing works
Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis
Rankin, A. L., Seth, N., Keegan, S., Andreyeva, T., Cook, T. A., Edmonds, J., Mathialagan, N., Benson, M. J., Syed, J., Zhan, Y., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301553 · Cited by 113 · see citing works
Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol
Goedken, E. R., Argiriadi, M. A., Banach, D. L., Fiamengo, B. A., Foley, S. E., Frank, K. E., George, J. S., Harris, C. M., Hobson, A. D., Ihle, D. C., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.595181 · Cited by 101 · see citing works
Liu, L., Paolo, J. A. D., Barbosa, J., Rong, H., Reif, K., & Wong, H. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.181545 · Cited by 89 · see citing works
Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non‐Hodgkin lymphoma
Zhang, S. Y., Smith, S. M., Zhang, S. Y., & Wang, Y. L. (2015) · British Journal of Haematology · doi:10.1111/bjh.13427 · Cited by 88 · see citing works
Lou, Y. C., Owens, T. D., Kuglstatter, A., Kondru, R. K., & GOLDSTEIN, D. M. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300035p · Cited by 88 · see citing works
Clinical perspectives for irreversible tyrosine kinase inhibitors in cancer
Carmi, C., Mor, M., Petronini, P. G., & Alfieri, R. R. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.07.031 · Cited by 76 · see citing works
Potent and selective Bruton’s tyrosine kinase inhibitors: Discovery of GDC-0834
Young, W. B., Barbosa, J., Blomgren, P., Bremer, M. C. D., Crawford, J. J., Dambach, D. M., Gallion, S., Hymowitz, S. G., Kropf, J. E., Lee, S., et al. (2015) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2015.01.032 · Cited by 68 · see citing works
Self-citationDiscovery of a Selective Irreversible BMX Inhibitor for Prostate Cancer
Liu, F., Zhang, X., Weisberg, E., Chen, S., Hur, W., Wu, H., Zhao, Z., Wang, W., Mao, M., Cai, C., et al. (2013) · ACS Chemical Biology · doi:10.1021/cb4000629 · Cited by 54 · see citing works
Hair and Nail Changes During Long-term Therapy With Ibrutinib for Chronic Lymphocytic Leukemia
Bitar, C., Farooqui, M. Z. H., Valdez, J., Saba, N. S., Soto, S., Bray, A., Marti, G. E., Wiestner, A. U., & Cowen, E. W. (2016) · JAMA Dermatology · doi:10.1001/jamadermatol.2016.0225 · Cited by 50 · see citing works
Young, W. B., Barbosa, J., Blomgren, P., Bremer, M. C. D., Crawford, J. J., Dambach, D. M., Eigenbrot, C. W., Gallion, S., Johnson, A. R., Kropf, J. E., et al. (2015) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2015.11.076 · Cited by 43 · see citing works
Self-citationChang, B. Y., Furman, R. R., Zapatka, M., Barrientos, J. C., Li, D., Steggerda, S. M., Eckert, K., Francesco, M. R., Woyach, J. A., Johnson, A. J., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2013.31.15_suppl.7014 · Cited by 36 · see citing works
Self-citationAdverse event potentially due to an interaction between ibrutinib and verapamil: a case report
Kuhn, E. L., Levêque, D., Lioure, B., et al. (2016) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/jcpt.12355 · Cited by 32 · see citing works
Bruton's TK Inhibitors: Structural Insights and Evolution of Clinical Candidates
Xing, L., & Huang, A. J. (2014) · Future Medicinal Chemistry · doi:10.4155/fmc.14.24 · Cited by 14 · see citing works
The clinical safety of ibrutinib in chronic lymphocytic leukemia
Molica, S. (2015) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2015.1084286 · Cited by 6 · see citing works
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- Authors
- Johnson, A. R., Kohli, P. B., Katewa, A., Gogol, E., Belmont, L. D., Choy, R., Penuel, E., Burton, L., Eigenbrot, C., Yu, C., Ortwine, D. F., Bowman, K., Franke, Y., Tam, C., Estevez, A., Mortara, K., Wu, J., Li, H., Lin, M., Bergeron, P., Crawford, J. J., & Young, W. B.
- Affiliations
- Genentech (US)
- Corresponding author
- Johnson, Adam R.
- ORCID
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-09-07
- Volume
- 11
- Issue
- 10
- Pages
- 2897-2907
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- OpenAlex
- W2518577288
- Cited by
- 137
- References
- 44
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 12 · 2023: 16 · 2022: 16 · 2021: 21 · 2020: 19 · 2019: 18 · 2018: 13 · 2017: 9 · 2016: 1
- FWCI
- 10.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- 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 › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- Bruton's tyrosine kinase, BTK inhibitors, ibrutinib resistance, non-covalent inhibitors, B-cell malignancies, B cell receptor signaling, kinase selectivity, inhibitor binding mode, crystal structure
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Adenine, Antineoplastic Agents, Cysteine, Humans, Kinetics, Mutation, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Threonine, Leukemia, Lymphocytic, Chronic, B-Cell, Protein Kinase Inhibitors
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