Table Info

Table 1.

Key clinical trials with ibrutinib in CLL

Name	Phase	Population	Response	Ref
N/A	IB/II	R/R^b	71% ORR^c by standard response criteria. Additional 18% partial response with persistent lymphocytosis	[62]
Resonate	III	R/R	Demonstrated that ibrutinib was superior to ofatumumab for response rate, PFS^d and OS^e	[63]
N/A	I/IB	TN^f ≥ 65 years	90% achieved objective response or partial response with persistent lymphocytosis	[64]
Resonate-2	III	TN ≥ 65 years	Demonstrated that ibrutinib was superior to chlorambucil for overall response rate, PFS and OS	[65]
Helios	III	R/R	Ibrutinib + bendamustine/rituximab superior to bendamustine/rituximab for PFS and OS	[66, 67]
Alliance A041202	III	TN ≥ 65 years	Ibrutinib superior to bendamustine + rituximab for PFS. No difference between ibrutinib or ibrutinib + rituximab for PFS	[68]
ECOG 1912	III	TN ≤ 70 years	Ibrutinib + rituximab superior to CIT for PFS and OS at interim analysis	[69]
iLLUMINATE	III	TN ≥ 65 years or < 65 years with coexisting conditions	Ibrutinib + obinutuzumab superior to chlorambucil + obinutuzumab for PFS	[70]

N/A: not applicable;

R/R: relapsed/refractory;

ORR: overall response rate;

PFS: progression-free survival;

OS: overall survival;

TN: treatment naïve

Declarations

Author contributions

GP wrote the first draft of the manuscript and RA, BVA and AJS wrote additional sections. All authors contributed to manuscript revision and approved the final version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Work in the authors laboratories on B-cell receptor signaling and its inhibition is funded by Cancer Research UK (C2750/A23669). The funders had no role in preparation of the manuscript.

Copyright

References

Kipps TJ, Stevenson FK, Wu CJ, Croce CM, Packham G, Wierda WG, et al. Chronic lymphocytic leukaemia. Nat Rev Dis Primers. 2017;3:17008. [DOI] [PubMed]

Paiva SL, Crews CM. Targeted protein degradation: elements of PROTAC design. Curr Opin Chem Biol. 2019;50:111–9. [DOI] [PubMed] [PMC]

Konstantinidou M, Li J, Zhang B, Wang Z, Shaabani S, Ter Brake F, et al. PROTACs– a game-changing technology. Expert Opin Drug Discov. 2019;14:1255–68. [DOI] [PubMed] [PMC]

Dikic I. Proteasomal and autophagic degradation systems. Annu Rev Biochem. 2017;86:193–224. [DOI] [PubMed]

Bondeson DP, Mares A, Smith IE, Ko E, Campos S, Miah AH, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol. 2015;11:611–7. [DOI] [PubMed] [PMC]

Bondeson DP, Smith BE, Burslem GM, Buhimschi AD, Hines J, Jaime-Figueroa S, et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem Biol. 2018;25:78–87.e5. [DOI] [PubMed] [PMC]

Gadd MS, Testa A, Lucas X, Chan KH, Chen W, Lamont DJ, et al. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat Chem Biol. 2017;13:514–21. [DOI] [PubMed] [PMC]

Huang HT, Dobrovolsky D, Paulk J, Yang G, Weisberg EL, Doctor ZM, et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem Biol. 2018;25:88–99.e6. [DOI] [PubMed] [PMC]

Crew AP, Raina K, Dong H, Qian Y, Wang J, Vigil D, et al. Identification and characterization of von hippel-lindau-recruiting proteolysis targeting chimeras (PROTACs) of TANK-binding kinase 1. J Med Chem. 2018;61:583–98. [DOI] [PubMed]

10.

Churcher I. Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones? J Med Chem. 2018;61:444–52. [DOI] [PubMed]

11.

Maple HJ, Clayden N, Baron A, Stacey C, Felix R. Developing degraders: principles and perspectives on design and chemical space. Medchemcomm. 2019;10:1755–64. [DOI] [PubMed] [PMC]

12.

Chessum NEA, Sharp SY, Caldwell JJ, Pasqua AE, Wilding B, Colombano G, et al. Demonstrating in-cell target engagement using a pirin protein degradation probe (CCT367766). J Med Chem. 2018;61:918–33. [DOI] [PubMed] [PMC]

13.

Puente XS, Jares P, Campo E. Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions. Blood. 2018;131:2283–96. [DOI] [PubMed]

14.

Pekarsky Y, Balatti V, Croce CM. BCL2 and miR-15/16: from gene discovery to treatment. Cell Death Differ. 2018;25:21–6. [DOI] [PubMed] [PMC]

15.

Te Raa GD, Kater AP. TP53 dysfunction in CLL: Implications for prognosis and treatment. Best Pract Res Clin Haematol. 2016;29:90–9. [DOI] [PubMed]

16.

Autore F, Strati P, Laurenti L, Ferrajoli A. Morphological, immunophenotypic, and genetic features of chronic lymphocytic leukemia with trisomy 12: a comprehensive review. Haematologica. 2018;103:931–8. [DOI] [PubMed] [PMC]

17.

Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526:525–30. [DOI] [PubMed] [PMC]

18.

Gaidano G, Rossi D. The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment. Hematology Am Soc Hematol Educ Program. 2017;2017:329–37. [DOI] [PubMed] [PMC]

19.

Ten Hacken E, Burger JA. Microenvironment interactions and B-cell receptor signaling in chronic lymphocytic leukemia: implications for disease pathogenesis and treatment. Biochim Biophys Acta. 2016;1863:401–13. [DOI] [PubMed] [PMC]

20.

Herishanu Y, Pérez-Galán P, Liu D, Biancotto A, Pittaluga S, Vire B, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117:563–74. [DOI] [PubMed] [PMC]

21.

Calissano C, Damle RN, Marsilio S, Yan XJ, Yancopoulos S, Hayes G, et al. Intraclonal complexity in chronic lymphocytic leukemia: fractions enriched in recently born/divided and older/quiescent cells. Mol Med. 2011;17:1374–82. [DOI] [PubMed] [PMC]

22.

Redondo-Muñoz J, Garcïa-Pardo A, Teixidó J. Molecular players in hematologic tumor cell trafficking. Front Immunol. 2019;10:156. [DOI] [PubMed] [PMC]

23.

Schieber M, Ma S. The expanding role of venetoclax in chronic lymphocytic leukemia and small lymphocytic lymphoma. Blood Lymphat Cancer. 2019;9:9–17. [DOI] [PubMed] [PMC]

24.

Arnason JE, Brown JR. Targeting B cell signaling in chronic lymphocytic leukemia. Curr Oncol Rep. 2017;19:61. [DOI] [PubMed]

25.

Young RM, Phelan JD, Wilson WH, Staudt LM. Pathogenic B-cell receptor signaling in lymphoid malignancies: New insights to improve treatment. Immunol Rev. 2019;291:190–213. [DOI] [PubMed] [PMC]

26.

Rickert RC. New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. Nat Rev Immunol. 2013;13:578–91. [DOI] [PubMed]

27.

Packham G, Krysov S, Allen A, Savelyeva N, Steele AJ, Forconi F, et al. The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy. Haematologica. 2014;99:1138–48. [DOI] [PubMed] [PMC]

28.

D'Avola A, Drennan S, Tracy I, Henderson I, Chiecchio L, Larrayoz M, et al. Surface IgM expression and function are associated with clinical behavior, genetic abnormalities, and DNA methylation in CLL. Blood. 2016;128:816–26. [DOI] [PubMed]

29.

Kurosaki T, Kurosaki M. Transphosphorylation of Bruton's tyrosine kinase on tyrosine 551 is critical for B cell antigen receptor function. J Biol Chem. 1997;272:15595–8. [DOI] [PubMed]

30.

Kurosaki T, Maeda A, Ishiai M, Hashimoto A, Inabe K, Takata M. Regulation of the phospholipase C-gamma2 pathway in B cells. Immunol Rev. 2000;176:19–29. [DOI] [PubMed]

31.

Scharenberg AM, Kinet JP. PtdIns-3,4,5-P3: a regulatory nexus between tyrosine kinases and sustained calcium signals. Cell. 1998;94:5–8. [DOI] [PubMed]

32.

Kurosaki T, Tsukada S. BLNK: connecting Syk and Btk to calcium signals. Immunity. 2000;12:1–5. [DOI] [PubMed]

33.

Rodriguez R, Matsuda M, Perisic O, Bravo J, Paul A, Jones NP, et al. Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling. J Biol Chem. 2001;276:47982–92. [DOI] [PubMed]

34.

Watanabe D, Hashimoto S, Ishiai M, Matsushita M, Baba Y, Kishimoto T, et al. Four tyrosine residues in phospholipase C-gamma 2, identified as Btk-dependent phosphorylation sites, are required for B cell antigen receptor-coupled calcium signaling. J Biol Chem. 2001;276:38595–601. [DOI] [PubMed]

35.

Smyth JT, Hwang SY, Tomita T, DeHaven WI, Mercer JC, Putney JW. Activation and regulation of store-operated calcium entry. J Cell Mol Med. 2010;14:2337–49. [DOI] [PubMed] [PMC]

36.

Baba Y, Kurosaki T. Impact of Ca²⁺ signaling on B cell function. Trends Immunol. 2011;32:589–94. [DOI] [PubMed]

37.

Scharenberg AM, Humphries LA, Rawlings DJ. Calcium signalling and cell-fate choice in B cells. Nat Rev Immunol. 2007;7:778–89. [DOI] [PubMed] [PMC]

38.

Duyao MP, Buckler AJ, Sonenshein GE. Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. Proc Natl Acad Sci U S A. 1990;87:4727–31. [DOI] [PubMed] [PMC]

39.

Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999;18:6853–66. [DOI] [PubMed]

40.

Vogler M. BCL2A1: the underdog in the BCL2 family. Cell Death Differ. 2012;19:67–74. [DOI] [PubMed] [PMC]

41.

Iwanaga R, Ozono E, Fujisawa J, Ikeda MA, Okamura N, Huang Y, et al. Activation of the cyclin D2 and cdk6 genes through NF-kappaB is critical for cell-cycle progression induced by HTLV-I Tax. Oncogene. 2008;27:5635–42. [DOI] [PubMed]

42.

Spaargaren M, Beuling EA, Rurup ML, Meijer HP, Klok MD, Middendorp S, et al. The B cell antigen receptor controls integrin activity through Btk and PLCgamma2. J Exp Med. 2003;198:1539–50. [DOI] [PubMed] [PMC]

43.

Guinamard R, Signoret N, Ishiai M, Marsh M, Kurosaki T, Ravetch JV. B cell antigen receptor engagement inhibits stromal cell-derived factor (SDF)-1alpha chemotaxis and promotes protein kinase C (PKC)-induced internalization of CXCR4. J Exp Med. 1999;189:1461–6. [DOI] [PubMed] [PMC]

44.

de Gorter DJ, Beuling EA, Kersseboom R, Middendorp S, van Gils JM, Hendriks RW, et al. Bruton's tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity. 2007;26:93–104. [DOI] [PubMed]

45.

Ortolano S, Hwang IY, Han SB, Kehrl JH. Roles for phosphoinositide 3-kinases, Bruton's tyrosine kinase, and Jun kinases in B lymphocyte chemotaxis and homing. Eur J Immunol. 2006;36:1285–95. [DOI] [PubMed]

46.

Jefferies CA, Doyle S, Brunner C, Dunne A, Brint E, Wietek C, et al. Bruton's tyrosine kinase is a Toll/ interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. J Biol Chem. 2003;278:26258–64. [DOI] [PubMed]

47.

Liu X, Zhan Z, Li D, Xu L, Ma F, Zhang P, et al. Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk. Nat Immunol. 2011;12:416–24. [DOI] [PubMed]

48.

Ren L, Campbell A, Fang H, Gautam S, Elavazhagan S, Fatehchand K, et al. Analysis of the effects of the Bruton's tyrosine kinase (Btk) inhibitor ibrutinib on monocyte fcgamma receptor (FcγR) function. J Biol Chem. 2016;291:3043–52. [DOI] [PubMed] [PMC]

49.

Goldmann L, Duan R, Kragh T, Wittmann G, Weber C, Lorenz R, et al. Oral Bruton tyrosine kinase inhibitors block activation of the platelet Fc receptor CD32a (FcγRIIA): a new option in HIT? Blood Adv. 2019;3:4021–33. [DOI] [PubMed] [PMC]

50.

Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010;107:13075–80. [DOI] [PubMed] [PMC]

51.

Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117:6287–96. [DOI] [PubMed] [PMC]

52.

Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119:1182–9. [DOI] [PubMed] [PMC]

53.

de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119:2590–4. [DOI] [PubMed]

54.

Yeomans A, Thirdborough SM, Valle-Argos B, Linley A, Krysov S, Hidalgo MS, et al. Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation. Blood. 2016;127:449–57. [DOI] [PubMed]

55.

Krysov S, Steele AJ, Coelho V, Linley A, Sanchez Hidalgo M, Carter M, et al. Stimulation of surface IgM of chronic lymphocytic leukemia cells induces an unfolded protein response dependent on BTK and SYK. Blood. 2014;124:3101–9. [DOI] [PubMed] [PMC]

56.

Bojarczuk K, Sasi BK, Gobessi S, Innocenti I, Pozzato G, Laurenti L, et al. BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199. Blood. 2016;127:3192–201. [DOI] [PubMed]

57.

Aguilar-Hernandez MM, Blunt MD, Dobson R, Yeomans A, Thirdborough S, Larrayoz M, et al. IL-4 enhances expression and function of surface IgM in CLL cells. Blood. 2016;127:3015–25. [DOI] [PubMed]

58.

Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122:2539–49. [DOI] [PubMed] [PMC]

59.

Long M, Beckwith K, Do P, Mundy BL, Gordon A, Lehman AM, et al. Ibrutinib treatment improves T cell number and function in CLL patients. J Clin Invest. 2017;127:3052–64. [DOI] [PubMed] [PMC]

60.

Chen J, Kinoshita T, Sukbuntherng J, Chang BY, Elias L. Ibrutinib Inhibits ERBB receptor tyrosine kinases and HER2-amplified breast cancer cell growth. Mol Cancer Ther. 2016;15:2835–44. [DOI] [PubMed]

61.

Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31:88–94. [DOI] [PubMed] [PMC]

62.

Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32–42. [DOI] [PubMed] [PMC]

63.

Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–23. [DOI] [PubMed] [PMC]

64.

O'Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15:48–58. [DOI] [PubMed] [PMC]

65.

Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–37. [DOI] [PubMed] [PMC]

66.

Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17:200–11. [DOI] [PubMed]

67.

Fraser G, Cramer P, Demirkan F, Silva RS, Grosicki S, Pristupa A, et al. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. 2019;33:969–80. [DOI] [PubMed] [PMC]

68.

Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517–28. [DOI] [PubMed] [PMC]

69.

Shanafelt TD, Wang XV, Kay NE, Hanson CA, O'Brien S, Barrientos J, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432–43. [DOI] [PubMed] [PMC]

70.

Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:43–56. [DOI] [PubMed]

71.

Mato AR, Nabhan C, Thompson MC, Lamanna N, Brander DM, Hill B, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103:874–9. [DOI] [PubMed] [PMC]

72.

Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80–7. [DOI] [PubMed] [PMC]

73.

Jain P, Keating M, Wierda W, Estrov Z, Ferrajoli A, Jain N, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125:2062–7. [DOI] [PubMed] [PMC]

74.

Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286–94. [DOI] [PubMed] [PMC]

75.

Lampson BL, Brown JR. Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia? Expert Rev Hematol. 2018;11:185–94. [DOI] [PubMed] [PMC]

76.

Walliser C, Hermkes E, Schade A, Wiese S, Deinzer J, Zapatka M, et al. The phospholipase Cγ2 mutants R665W and L845F identified in ibrutinib-resistant chronic lymphocytic leukemia patients are hypersensitive to the Rho GTPase Rac2 protein. J Biol Chem. 2016;291:22136–48. [DOI] [PubMed] [PMC]

77.

Brown JR, Moslehi J, O'Brien S, Ghia P, Hillmen P, Cymbalista F, et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017;102:1796–805. [DOI] [PubMed] [PMC]

78.

McMullen JR, Boey EJ, Ooi JY, Seymour JF, Keating MJ, Tam CS. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124:3829–30. [DOI] [PubMed]

79.

Conley ME, Dobbs AK, Farmer DM, Kilic S, Paris K, Grigoriadou S, et al. Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol. 2009;27:199–227. [DOI] [PubMed]

80.

Atkinson BT, Ellmeier W, Watson SP. Tec regulates platelet activation by GPVI in the absence of Btk. Blood. 2003;102:3592–9. [DOI] [PubMed]

81.

Quek LS, Bolen J, Watson SP. A role for Bruton's tyrosine kinase (Btk) in platelet activation by collagen. Curr Biol. 1998;8:1137–40. [DOI] [PubMed]

82.

Bond DA, Woyach JA. Targeting BTK in CLL: beyond ibrutinib. Curr Hematol Malig Rep. 2019;14:197–205. [DOI] [PubMed]

83.

Isfort S, Crysandt M, Gezer D, Koschmieder S, Brummendorf TH, Wolf D. Bosutinib: A potent second-generation tyrosine kinase inhibitor. Recent Results Cancer Res. 2018;212:87–108. [DOI] [PubMed]

84.

Lou Y, Han X, Kuglstatter A, Kondru RK, Sweeney ZK, Soth M, et al. Structure-based drug design of RN486, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis. J Med Chem. 2015;58:512–6. [DOI] [PubMed]

85.

Chamberlain PP, Lopez-Girona A, Miller K, Carmel G, Pagarigan B, Chie-Leon B, et al. Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol. 2014;21:803–9. [DOI] [PubMed]

86.

Burslem GM, Smith BE, Lai AC, Jaime-Figueroa S, McQuaid DC, Bondeson DP, et al. The advantages of targeted protein degradation over inhibition: an RTK case study. Cell Chem Biol. 2018;25:67–77.e3. [DOI] [PubMed] [PMC]

87.

Buhimschi AD, Armstrong HA, Toure M, Jaime-Figueroa S, Chen TL, Lehman AM, et al. Targeting the C481S ibrutinib-resistance mutation in Bruton's tyrosine kinase using PROTAC-mediated degradation. Biochemistry. 2018;57:3564–75. [DOI] [PubMed]

88.

Jaime-Figueroa S, Buhimschi AD, Toure M, Hines J, Crews CM. Design, synthesis and biological evaluation of proteolysis targeting chimeras (PROTACs) as a BTK degraders with improved pharmacokinetic properties. Bioorg Med Chem Lett. 2020;30:126877. [DOI] [PubMed]

89.

Sun Y, Zhao X, Ding N, Gao H, Wu Y, Yang Y, et al. PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Res. 2018;28:779–81. [DOI] [PubMed] [PMC]

90.

Brown JR, Harb WA, Hill BT, Gabrilove J, Sharman JP, Schreeder MT, et al. Phase I study of single-agent CC-292, a highly selective Bruton's tyrosine kinase inhibitor, in relapsed/refractory chronic lymphocytic leukemia. Haematologica. 2016;101:e295–8. [DOI] [PubMed] [PMC]

91.

Sun Y, Ding N, Song Y, Yang Z, Liu W, Zhu J, et al. Degradation of Bruton's tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas. Leukemia. 2019;33:2105–10. [DOI] [PubMed]

92.

Roy MJ, Winkler S, Hughes SJ, Whitworth C, Galant M, Farnaby W, et al. SPR-measured dissociation kinetics of PROTAC ternary complexes influence target degradation rate. ACS Chem Biol. 2019;14:361–8. [DOI] [PubMed] [PMC]

93.

Zorba A, Nguyen C, Xu Y, Starr J, Borzilleri K, Smith J, et al. Delineating the role of cooperativity in the design of potent PROTACs for BTK. Proc Natl Acad Sci U S A. 2018;115:E7285–92. [DOI] [PubMed] [PMC]

94.

Rankin AL, Seth N, Keegan S, Andreyeva T, Cook TA, Edmonds J, et al. Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis. J Immunol. 2013;191:4540–50. [DOI] [PubMed]

95.

Tinworth CP, Lithgow H, Dittus L, Bassi ZI, Hughes SE, Muelbaier M, et al. PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding. ACS Chem Biol. 2019;14:342–7. [DOI] [PubMed]

96.

Xue G, Chen J, Liu L, Zhou D, Zuo Y, Fu T, et al. Protein degradation through covalent inhibitor-based PROTACs. Chem Commun (Camb). 2020;56:1521–4. [DOI] [PubMed]

97.

Ding N, Li X, Shi Y, Ping L, Wu L, Fu K, et al. Irreversible dual inhibitory mode: the novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma. Oncotarget. 2015;6:15122–36. [DOI] [PubMed] [PMC]

98.

Neklesa TK, Winkler JD, Crews CM. Targeted protein degradation by PROTACs. Pharmacol Ther. 2017;174:138–44. [DOI] [PubMed]

99.

Scheepstra M, Hekking KFW, van Hijfte L, Folmer RHA. Bivalent ligands for protein degradation in drug discovery. Comput Struct Biotechnol J. 2019;17:160–76. [DOI] [PubMed] [PMC]

100.

Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov. 2017;16:101–14. [DOI] [PubMed] [PMC]

101.

Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019;25:1938–47. [DOI] [PubMed] [PMC]