Targeting the C481S ibrutinib-resistance mutation in Bruton’s tyrosine kinase using PROTAC-mediated degradation
Abstract
Inhibition of Bruton's tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has emerged as a transformative treatment option for patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies, yet >80% of CLL patients develop resistance due to a cysteine to serine mutation at the site covalently bound by ibrutinib (C481S). Currently, an effective treatment option for C481S patients exhibiting relapse to ibrutinib does not exist, and these patients have poor outcomes. To address this, we have developed a PROteolysis TArgeting Chimera (PROTAC) that induces degradation of both wild-type and C481S mutant BTK. We selected a lead PROTAC, MT-802, from several candidates on the basis of its potency to induce BTK knockdown. MT-802 recruits BTK to the cereblon E3 ubiquitin ligase complex to trigger BTK ubiquitination and degradation via the proteasome. MT-802 binds fewer off-target kinases than ibrutinib does and retains an equivalent potency (>99% degradation at nanomolar concentrations) against wild-type and C481S BTK. In cells isolated from CLL patients with the C481S mutation, MT-802 is able to reduce the pool of active, phosphorylated BTK whereas ibrutinib cannot. Collectively, these data provide a basis for further preclinical study of BTK PROTACs as a novel strategy for treatment of C481S mutant CLL.
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Several studies reported successful conversion of either a reversible ibrutinib scaffold or a different noncovalent analog derived from a previously published covalent BTK inhibitor into BTK degraders.
“Subsequently, several studies reported successful conversion of either a reversible ibrutinib scaffold 42,43 or a different noncovalent analog derived from a previously published covalent BTK inhibitor 44,45 into BTK degraders.”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [42]
The C481S resistance mutation in BTK renders first-generation BTK inhibitors less effective.
“particularly because of emergence of the C481S resistance mutation in BTK that renders first-generation BTK inhibitors less effective169,170.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [169]
MT-802, but not ibrutinib, reduces activated-BTK levels in patient-derived CLL cells harboring the C481S mutation.
“MT-802, but not ibrutinib, was found to reduce activated-BTK levels in patient-derived CLL cells harboring the C481S mutation [116].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [116]
MT-802 is equally effective in degrading both wild-type and C418S mutated BTK.
“MT-802, a lead BTK PROTAC developed by Crews’ group, was shown to be equally effective in degrading both wild-type and C418S mutated BTK.”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [116]
Several PROTACs targeting BTK to CRBN have been generated and exhibit the potential to treat ibrutinib-resistant non-Hodgkin's lymphomas.
“several PROTACs targeting BTK, a protein that is important for normal B cell development and development of B cell lymphoma, to CRBN have been generated and exhibit the potential to treat ibrutinib-resistant non-Hodgkin’s lymphomas [6, 92].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [6]
Cites
Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141230798 · Cited by 2,609 · see citing works
Self-citationComprehensive analysis of kinase inhibitor selectivity
Davis, M. I., Hunt, J. P., Herrgard, S., Ciceri, P., Wodicka, L. M., Pallares, G., Hocker, M., Treiber, D. K., & Zarrinkar, P. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1990 · Cited by 2,409 · 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-citationLenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
Krönke, J., Udeshi, N. D., Narla, A., Grauman, P., Hurst, S. N., McConkey, M., Svinkina, T., Heckl, D., Comer, E., Li, X., et al. (2014) · Science · doi:10.1126/science.1244851 · Cited by 1,879 · see citing works
Phthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760 · see citing works
Differential activation of transcription factors induced by Ca2+ response amplitude and duration
Dolmetsch, R. E., Lewis, R. S., Goodnow, C. C., & Healy, J. I. (1997) · Nature · doi:10.1038/386855a0 · Cited by 1,754 · see citing works
The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins
Lu, G., Middleton, R. E., Sun, H., Naniong, M., Ott, C. J., Mitsiades, C. S., Wong, K.-K., Bradner, J. E., & Kaelin, W. G. (2014) · Science · doi:10.1126/science.1244917 · Cited by 1,583 · 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
Differential activation of transcription factors induced by Ca2+ response amplitude and duration
Dolmetsch, R. E., Lewis, R. S., Goodnow, C. C., & Healy, J. I. (1997) · Nature · doi:10.1038/40912 · Cited by 1,521 · see citing works
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486 · see citing works
Self-citationCatalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356 · see citing works
Self-citationResistance 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-citationStructural basis of PROTAC cooperative recognition for selective protein degradation
Gadd, M. S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D. J., Zengerle, M., & Ciulli, A. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2329 · Cited by 1,242 · see citing works
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., Hines, J., Winkler, J. D., Crew, A. P., Coleman, K., et al. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2015.05.009 · Cited by 1,140 · see citing works
Self-citationFDA-approved small-molecule kinase inhibitors
Wu, P., Nielsen, T. E., & Clausen, M. H. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.04.005 · Cited by 1,028 · see citing works
Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity
Meng, L., Mohan, R., Kwok, B. H. B., Elofsson, M., Sin, N., & Crews, C. M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.18.10403 · Cited by 926 · see citing works
Self-citationLessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead
Bondeson, D. P., Smith, B. E., Burslem, G. M., Buhimschi, A. D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B. D., Ishchenko, A., & Crews, C. M. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.010 · Cited by 923 · see citing works
Self-citationComprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity
Anastassiadis, T., Deacon, S. W., Devarajan, K., Ma, H., & Peterson, J. R. (2011) · Nature Biotechnology · doi:10.1038/nbt.2017 · Cited by 919 · see citing works
PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer
Raina, K., Lu, J., Qian, Y., Altieri, M., Gordon, D., Rossi, A. M. K., Wang, J., Chen, X., Dong, H., Siu, K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521738113 · Cited by 852 · see citing works
Self-citationDubovsky, J. A., Beckwith, K. A., Natarajan, G., Woyach, J. A., Jaglowski, S., Zhong, Y., Hessler, J. D., Liu, T.-M., Chang, B. Y., Larkin, K. M., et al. (2013) · Blood · doi:10.1182/blood-2013-06-507947 · Cited by 810 · 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
The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study
Burslem, G. M., Smith, B. E., Lai, A. C., Jaime-Figueroa, S., McQuaid, D. C., Bondeson, D. P., Toure, M., Dong, H., Qian, Y., Wang, J., et al. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.009 · Cited by 686 · see citing works
Self-citationSchneekloth, A. R., Pucheault, M., Tae, H. S., & Crews, C. M. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.07.114 · Cited by 635 · see citing works
Self-citationModular PROTAC design for the degradation of oncogenic BCR-ABL
Lai, A. C., Toure, M., Hellerschmied, D., Salami, J., Jaime‐Figueroa, S., Ko, E., Hines, J., & Crews, C. M. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201507634 · Cited by 618 · see citing works
Self-citationMaddocks, 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-citationBuckley, D. L., Van Molle, I., Gareiss, P. C., Tae, H. S., Michel, J., Noblin, D. J., Jorgensen, W. L., Ciulli, A., & Crews, C. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja209924v · Cited by 569 · see citing works
Self-citationChamberlain, P. P., Lopez-Girona, A., Miller, K., Carmel, G., Pagarigan, B., Chie-Leon, B., Rychak, E., Corral, L. G., Ren, Y. J., Wang, M., et al. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2874 · Cited by 531 · see citing works
Chen, L., Widhopf, G. F., Huynh, L., Rassenti, L. Z., Rai, K. R., Weiss, A., & Kipps, T. J. (2002) · Blood · doi:10.1182/blood-2002-06-1683 · Cited by 516 · see citing works
Mohamed, A. J., Yu, L., Bäckesjö, C., Vargas, L., Faryal, R., Aints, A., Christensson, B., Berglöf, A., Vihinen, M., Nore, B. F., et al. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00741.x · Cited by 516 · see citing works
Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?
Churcher, I. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01272 · Cited by 491 · see citing works
HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins
Buckley, D. L., Raina, K., Darricarrere, N., Hines, J., Gustafson, J. L., Smith, I. E., Miah, A. H., Harling, J. D., & Crews, C. M. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00442 · Cited by 488 · see citing works
Self-citationA Comprehensive Mathematical Model for Three-Body Binding Equilibria
Douglass, E. F., Miller, C. J., Sparer, G., Shapiro, H., & Spiegel, D. A. (2013) · Journal of the American Chemical Society · doi:10.1021/ja311795d · Cited by 472 · see citing works
A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader
Huang, H.-T., Dobrovolsky, D., Paulk, J., Yang, G., Weisberg, E. L., Doctor, Z. M., Buckley, D. L., Cho, J.-H., Ko, E., Jang, J., et al. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.10.005 · Cited by 437 · see citing works
Development of Protacs to Target Cancer-promoting Proteins for Ubiquitination and Degradation
Sakamoto, K. M., Kim, K. B., Verma, R., Ransick, A., Stein, B., Crews, C. M., & Deshaies, R. J. (2003) · Molecular & Cellular Proteomics · doi:10.1074/mcp.t300009-mcp200 · Cited by 425 · see citing works
Self-citationTargeted Protein Degradation: from Chemical Biology to Drug Discovery
Cromm, P. M., & Crews, C. M. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.05.024 · Cited by 423 · see citing works
Self-citationMcMullen, 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
Zhou, B. N., Hu, J., Xu, F., Chen, Z., Bai, L., Fernández‐Salas, E., Lin, M., Liu, L., Yang, C., Zhao, Y., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01816 · Cited by 373 · see citing works
A 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
Burger, J. A., Landau, D. A., Taylor-Weiner, A., Bozic, I., Zhang, H., Sarosiek, K., Wang, L., Stewart, C., Fan, J., Hoellenriegel, J., et al. (2016) · Nature Communications · doi:10.1038/ncomms11589 · Cited by 345 · see citing works
Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib
Jain, P., Keating, M. J., Wierda, W. G., Estrov, Z. E., Ferrajoli, A., Jain, N., George, B., James, D. F., Kantarjian, H. M., Burger, J. A., et al. (2015) · Blood · doi:10.1182/blood-2014-09-603670 · Cited by 335 · see citing works
Small‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α
Buckley, D. L., Gustafson, J. L., Van Molle, I., Roth, A. G., Tae, H. S., Gareiss, P. C., Jorgensen, W. L., Ciulli, A., & Crews, C. M. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201206231 · Cited by 302 · see citing works
Self-citationIbrutinib 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
Byrd, J. C., Shinn, C. A., Waselenko, J. K., et al. (1998) · Blood · doi:10.1182/blood.v92.10.3804 · Cited by 282 · see citing works
Self-citationWaste disposal—An attractive strategy for cancer therapy
Salami, J., & Crews, C. M. (2017) · Science · doi:10.1126/science.aam7340 · Cited by 279 · see citing works
Self-citationCrawford, J. J., Johnson, A. R., Misner, D., Belmont, L. D., Castanedo, G. M., Choy, R., Coraggio, M., Dong, L., Eigenbrot, C. W., Erickson, R., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01712 · Cited by 263 · see citing works
Self-citationOhoka, N., Okuhira, K., Ito, M., Nagai, K., Shibata, N., Hattori, T., Ujikawa, O., Shimokawa, K., Sano, O., Koyama, R., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.768853 · Cited by 240 · see citing works
Woyach, J. A., Bojnik, E., Ruppert, A. S., Stefanovski, M. R., Goettl, V. M., Smucker, K. A., Smith, L. L., Dubovsky, J. A., Towns, W. H., MacMurray, J., et al. (2013) · Blood · doi:10.1182/blood-2013-07-515361 · Cited by 222 · see citing works
Self-citationAssessing Different E3 Ligases for Small Molecule Induced Protein Ubiquitination and Degradation
Ottis, P., Toure, M., Cromm, P. M., Ko, E., Gustafson, J. L., & Crews, C. M. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.7b00485 · Cited by 176 · see citing works
Self-citationPatel, V. M., Balakrishnan, K., Бибикова, Е., Ayres, M., Keating, M. J., Wierda, W. G., & Gandhi, V. V. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1446 · Cited by 151 · see citing works
Battling Btk mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations
Johnson, A. R., Kohli, P. B., Katewa, A., Gogol, E., Belmont, L. D., Choy, R., Penuel, E., Burton, L., Eigenbrot, C., Yu, C., et al. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.6b00480 · Cited by 137 · see citing works
Self-citationWatanabe, D., Hashimoto, S., Ishiai, M., Matsushita, M., Baba, Y., Kishimoto, T., Kurosaki, T., & Tsukada, S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103675200 · Cited by 136 · see citing works
Kurosaki, T., & Kurosaki, M. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.25.15595 · Cited by 133 · see citing works
Inactivation of PI3Kγ and PI3Kδ distorts T-cell development and causes multiple organ inflammation
Ji, H., Rintelen, F., Waltzinger, C., Bertschy‐Meier, D., Bilancio, A., Pearce, W. P., Hirsch, E., Wymann, M. P., Rückle, T., Camps, M., et al. (2007) · Blood · doi:10.1182/blood-2007-04-086751 · Cited by 115 · see citing works
Krysov, S. V., Dias, S., Paterson, A. R., Mockridge, C. I., Potter, K. N., Smith, K.-A., Ashton‐Key, M., Stevenson, F. K., & Packham, G. (2011) · Blood · doi:10.1182/blood-2011-07-370403 · Cited by 99 · see citing works
IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells
Dong, S., Guinn, D., Dubovsky, J. A., Zhong, Y., Lehman, A., Kutok, J. L., Woyach, J. A., Byrd, J. C., & Johnson, A. J. (2014) · Blood · doi:10.1182/blood-2014-07-587279 · Cited by 98 · see citing works
Self-citationIbrutinib Inhibits ERBB Receptor Tyrosine Kinases and HER2-Amplified Breast Cancer Cell Growth
Chen, J., Kinoshita, T., Sukbuntherng, J., Chang, B. Y., & Elias, L. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0923 · Cited by 93 · see citing works
Thompson, P. A., & Burger, J. A. (2017) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2018.1404027 · Cited by 65 · see citing works
Byrd, J. C., Shinn, C. A., Waselenko, J. K., et al. (1998) · Blood · doi:10.1182/blood.v92.10.3804.422k36_3804_3816 · Cited by 62 · see citing works
Self-citationXu, J., Wang, J., & Zhang, S. (2017) · Oncotarget · doi:10.18632/oncotarget.21164 · Cited by 48 · see citing works
Current Status of Bruton’s Tyrosine Kinase Inhibitor Development and Use in B-Cell Malignancies
Aw, A., & Brown, J. R. (2017) · Drugs & Aging · doi:10.1007/s40266-017-0468-4 · Cited by 42 · see citing works
Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia
Maddocks, K. J., & Jones, J. A. (2016) · Seminars in Oncology · doi:10.1053/j.seminoncol.2016.02.008 · Cited by 32 · see citing works
Recent therapeutic advances in chronic lymphocytic leukemia
Bose, P., & Gandhi, V. V. (2017) · F1000Research · doi:10.12688/f1000research.11618.1 · Cited by 16 · see citing works
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Tinworth, C. P., Lithgow, H., Dittus, L., Bassi, Z. I., Hughes, S. E., Muelbaier, M., Dai, H., Smith, I. E. D., Kerr, W. J., Burley, G. A., et al. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.8b01094 · Cited by 195 · see citing works
Harnessing the Power of Proteolysis for Targeted Protein Inactivation
Verma, R., Mohl, D., & Deshaies, R. J. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.01.010 · Cited by 185 · see citing works
Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras
Samarasinghe, K. T. G., Jaime-Figueroa, S., Burgess, M., Nalawansha, D. A., Dai, K., Hu, Z., Bebenek, A., Holley, S. A., & Crews, C. M. (2021) · Cell Chemical Biology · doi:10.1016/j.chembiol.2021.03.011 · Cited by 182 · see citing works
Self-citationKinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127
Montoya, S., Bourcier, J., Noviski, M., Lu, H., Thompson, M. C., Chirino, A., Jahn, J., Sondhi, A. K., Gajewski, S., Tan, Y. S. (., et al. (2024) · Science · doi:10.1126/science.adi5798 · Cited by 175 · see citing works
Burslem, G. M., Song, J., Chen, X., Hines, J., & Crews, C. M. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b10320 · Cited by 176 · see citing works
Self-citationBruton tyrosine kinase degradation as a therapeutic strategy for cancer
Dobrovolsky, D., Wang, E. S., Morrow, S., Leahy, C., Faust, T., Nowak, R. P., Donovan, K. A., Yang, G., Li, Z., Fischer, E. S., et al. (2019) · Blood · doi:10.1182/blood-2018-07-862953 · Cited by 169 · see citing works
Drummond, M. L., Henry, A., Li, H., & Williams, C. I. (2020) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c00897 · Cited by 166 · see citing works
Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta
Bai, N., Miller, S. A., Andrianov, G. V., Yates, M., Kirubakaran, P., & Karanicolas, J. (2021) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c01451 · Cited by 157 · see citing works
Sun, Y., Ding, N., Song, Y., Yang, Z., Liu, W., Zhu, J., & Rao, Y. (2019) · Leukemia · doi:10.1038/s41375-019-0440-x · Cited by 148 · see citing works
Mutant-selective degradation by BRAF-targeting PROTACs
Alabi, S., Jaime-Figueroa, S., Yao, Z., Gao, Y., Hines, J., Samarasinghe, K. T. G., Vogt, L., Rosen, N., & Crews, C. M. (2021) · Nature Communications · doi:10.1038/s41467-021-21159-7 · Cited by 152 · see citing works
Self-citationCancer therapies based on targeted protein degradation — lessons learned with lenalidomide
Jan, M., Sperling, A. S., & Ebert, B. L. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00479-z · Cited by 137 · see citing works
Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs)
Chen, P.-H., Hu, Z., An, E., Okeke, I., Zheng, S., Luo, X., Gong, A., Jaime-Figueroa, S., & Crews, C. M. (2021) · ACS Chemical Biology · doi:10.1021/acschembio.1c00693 · Cited by 130 · see citing works
Self-citationZhao, Q., Ren, C., Liu, L., Chen, J., Shao, Y., Sun, N., Sun, R., Kong, Y., Ding, X., Zhang, X., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01264 · Cited by 134 · see citing works
Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies
He, Y., Khan, S., Huo, Z., Lv, D., Zhang, X., Liu, X., Yuan, Y., Hromas, R., Xu, M., Zheng, G., et al. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00924-z · Cited by 126 · see citing works
Peptide-based PROTAC degrader of FOXM1 suppresses cancer and decreases GLUT1 and PD-L1 expression
Wang, K., Dai, X., Yu, A., Feng, C., Liu, K., & Huang, L. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02483-2 · Cited by 115 · see citing works
Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes
Schiemer, J., Horst, R., Meng, Y., Montgomery, J. I., Xu, Y., Feng, X., Borzilleri, K., Uccello, D. P., Leverett, C., Brown, S., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-020-00686-2 · Cited by 113 · see citing works
Jaime-Figueroa, S., Buhimschi, A. D., Toure, M., Hines, J., & Crews, C. M. (2020) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.126877 · Cited by 88 · see citing works
Self-citationScrutinizing the Therapeutic Potential of PROTACs in the Management of Alzheimer’s Disease
Bhatia, S., Singh, M., Singh, T., & Singh, V. (2023) · Neurochemical Research · doi:10.1007/s11064-022-03722-w · Cited by 22 · see citing works
Wang, Y., Deng, S., & Xu, J. (2020) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2020.0066 · Cited by 10 · see citing works
- Authors
- Buhimschi, A. D., Armstrong, H. A., Toure, M., Jaime-Figueroa, S., Chen, T. L., Lehman, A. M., Woyach, J. A., Johnson, A. J., Byrd, J. C., & Crews, C. M.
- Affiliations
- Yale University (US)
- The Ohio State University (US)
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06511, United States
- Corresponding author
- Byrd, John C.
- Crews, Craig M.
- ORCID
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-05-31
- Volume
- 57
- Issue
- 26
- Pages
- 3564-3575
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2805296794
- Cited by
- 394
- References
- 63
- Citations by year
- 2026: 33 · 2025: 55 · 2024: 56 · 2023: 44 · 2022: 59 · 2021: 55 · 2020: 47 · 2019: 35 · 2018: 8 · 2014: 1
- FWCI
- 20.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R35CA197589)
- Arvinas, Inc.
- 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
- Bruton's tyrosine kinase, ibrutinib resistance, PROTACs, chronic lymphocytic leukemia, proteasomal degradation, BTK phosphorylation, B-cell malignancies
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Adenine, Humans, Piperidines, Pyrazoles, Pyrimidines, Drug Design, Leukemia, Lymphocytic, Chronic, B-Cell, Point Mutation, Drug Resistance, Neoplasm, Amino Acid Substitution, Cell Line, Tumor, Protein Kinase Inhibitors, Ubiquitination, Proteolysis, Molecular Docking Simulation
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