Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR) signaling pathway, crucial for B-cell survival and proliferation. The first-in-class irreversible BTK inhibitor, ibrutinib, was approved for various B-cell malignancies but has limitations due to off-target effects. Second-generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti-CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis-targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK-targeted therapies provide hope for improved outcomes in patients with B-cell malignancies and a promising avenue to address drug resistance. Further research is needed to optimize combination therapies and identify optimal treatment regimens.

Department of Experimental Biology Faculty of Science Palacký University Olomouc Olomouc Czech Republic

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Woyach JA, Johnson AJ. Targeted therapies in CLL: mechanisms of resistance and strategies for management. Blood. 2015;126(4):471‐477. https://doi.org/10.1182/blood‐2015‐03‐585075

Nakhoda S, Vistarop A, Wang YL. Resistance to Bruton tyrosine kinase inhibition in chronic lymphocytic leukaemia and non‐Hodgkin lymphoma. Br J Haematol. 2023;200(2):137‐149. https://doi.org/10.1111/bjh.18418

Stephens DM, Byrd JC. Resistance to Bruton tyrosine kinase inhibitors: the Achilles heel of their success story in lymphoid malignancies. Blood. 2021;138(13):1099‐1109. https://doi.org/10.1182/blood.2020006783

Wang Q, Pechersky Y, Sagawa S, Pan AC, Shaw DE. Structural mechanism for Bruton’s tyrosine kinase activation at the cell membrane. Proc Natl Acad Sci USA. 2016;116(19):9390‐9399. https://doi.org/10.1073/pnas.1819301116

Lee HJ, Gallardo M, Ma H, et al. p53‐independent ibrutinib responses in an Eμ‐TCL1 mouse model demonstrates efficacy in high‐risk CLL. Blood Cancer J. 2016;6(6):e434. https://doi.org/10.1038/bcj.2016.41

Honigberg LA, Smith AM, Sirisawad M, 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 USA. 2010;107(29):13075‐13080. https://doi.org/10.1073/pnas.1004594107

Chang BY, Francesco M, De Rooij MFM, et al. Egress of CD19+CD5+ cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013;122(14):2412‐2424. https://doi.org/10.1182/blood‐2013‐02‐482125

Ponader S, Chen S.‐S, Buggy JJ, 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(5):1182‐1189. https://doi.org/10.1182/blood‐2011‐10‐386417

Xiao L, Salem J.‐E, Clauss S, et al. Ibrutinib‐mediated atrial fibrillation attributable to inhibition of C‐terminal src kinase. Circulation. 2020;142(25):2443‐2455. https://doi.org/10.1161/CIRCULATIONAHA.120.049210

Singer S, Tan SY, Dewan AK, et al. Cutaneous eruptions from ibrutinib resembling epidermal growth factor receptor inhibitor–induced dermatologic adverse events. J Am Acad Dermatol. 2023;88(6):1271‐1281. https://doi.org/10.1016/j.jaad.2019.12.031

Lipsky A, Lamanna N. Managing toxicities of Bruton tyrosine kinase inhibitors. Hematology. 2020;2020(1):336‐345. https://doi.org/10.1182/hematology.2020000118

Herman SEM, Montraveta A, Niemann CU, et al. The Bruton tyrosine kinase (BTK) inhibitor acalabrutinib demonstrates potent on‐target effects and efficacy in two mouse models of chronic lymphocytic leukemia. Clin Cancer Res. 2017;23(11):2831‐2841. https://doi.org/10.1158/1078‐0432.CCR‐16‐0463

Awan FT, Schuh A, Brown JR, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019;3(9):1553‐1562. https://doi.org/10.1182/bloodadvances.2018030007

Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441‐3452. https://doi.org/10.1200/JCO.21.01210

Kaptein A, de Bruin G, Emmelot‐van Hoek M, et al. Potency and selectivity of BTK inhibitors in clinical development for B‐cell malignancies. Blood. 2018;132(suppl 1):1871. https://doi.org/10.1182/blood‐2018‐99‐109973

Hillmen P, Brown JR, Eichhorst BF, et al. ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Future Oncol. 2020;16(10):517‐523. https://doi.org/10.2217/fon‐2019‐0844

Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038‐2050. https://doi.org/10.1182/blood.2020006844

Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319‐332. https://doi.org/10.1056/NEJMoa2211582

Shadman M, Flinn IW, Levy MY, et al. Zanubrutinib in patients with previously treated B‐cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open‐label, single‐arm study. Lancet Haematol. 2023;10(1):e35‐e45. https://doi.org/10.1016/S2352‐3026(22)00320‐9

Burger JA, Barr PM, Robak T, et al. Long‐term efficacy and safety of first‐line ibrutinib treatment for patients with CLL/SLL: 5 years of follow‐up from the phase 3 RESONATE‐2 study. Leukemia. 2020;34(3):787‐798. https://doi.org/10.1038/s41375‐019‐0602‐x

Housman G, Byler S, Heerboth S, et al. Drug resistance in cancer: an overview. Cancers. 2014;6(3):1769‐1792. https://doi.org/10.3390/cancers6031769

Hershkovitz‐Rokah O, Pulver D, Lenz G, Shpilberg O. Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects. Br J Haematol. 2018;181(3):306‐319. https://doi.org/10.1111/bjh.15108

Woyach J, Huang Y, Rogers K, et al. Resistance to acalabrutinib in CLL is mediated primarily by BTK mutations. Blood. 2019;134(suppl 1):504. https://doi.org/10.1182/blood‐2019‐127674

Furman RR, Cheng S, Lu P, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370(24):2352‐2354. https://doi.org/10.1056/nejmc1402716

Cheng S, Guo A, Lu P, Ma J, Coleman M, Wang YL. Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia. 2015;29(4):895‐900. https://doi.org/10.1038/leu.2014.263

Qi J, Endres S, Yosifov DY, et al. Acquired BTK mutations associated with resistance to noncovalent BTK inhibitors. Blood Adv. 2023;7(19):5698‐5702. https://doi.org/10.1182/bloodadvances.2022008955

Gángó A, Alpár D, Galik B, et al. Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib. Int J Cancer. 2020;146(1):85‐93. https://doi.org/10.1002/ijc.32502

Wang H, Zhang W, Yang J, Zhou K. The resistance mechanisms and treatment strategies of BTK inhibitors in B‐cell lymphoma. Hematol Oncol. 2021;39(5):605‐615. https://doi.org/10.1002/hon.2933

Sedlarikova L, Petrackova A, Papajik T, Turcsanyi P, Kriegova E. Resistance‐associated mutations in chronic lymphocytic leukemia patients treated with novel agents. Front Oncol. 2020;10:894. https://doi.org/10.3389/fonc.2020.00894

Wang E, Mi X, Thompson MC, et al. Mechanisms of resistance to noncovalent bruton’s tyrosine kinase inhibitors. N Engl J Med. 2022;386(8):735‐743. https://doi.org/10.1056/NEJMoa2114110

Estupiñán HY, Wang Q, Berglöf A, et al. BTK gatekeeper residue variation combined with cysteine 481 substitution causes super‐resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib. Leukemia. 2021;35(5):1317‐1329. https://doi.org/10.1038/s41375‐021‐01123‐6

Aslan B, Hubner SE, Fox JA, et al. Vecabrutinib inhibits B‐cell receptor signal transduction in chronic lymphocytic leukemia cell types with wild‐type or mutant Bruton tyrosine kinase. Haematologica. 2021;107(1):292‐297. https://doi.org/10.3324/haematol.2021.279158

Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1(1):80. https://doi.org/10.1001/jamaoncol.2014.218

Woyach JA, Furman RR, Liu T.‐M, et al. Resistance mechanisms for the bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286‐2294. https://doi.org/10.1056/NEJMoa1400029

Montoya S, Bourcier J, Noviski M, et al. Kinase‐impaired BTK mutations are susceptible to clinical‐stage BTK and IKZF1/3 degrader NX‐2127. Science. 2024;383(6682):eadi5798. https://10.1126/science.adi5798

Handunnetti SM, Tang CPS, Nguyen T, et al. BTK Leu528Trp ‐ a potential secondary resistance mechanism specific for patients with chronic lymphocytic leukemia treated with the next generation BTK inhibitor zanubrutinib. Blood. 2019;134(suppl 1):170. https://doi.org/10.1182/blood‐2019‐125488

Song Y, Sun M, Qi J, et al. A two‐part, single‐arm, multicentre, phase I study of zanubrutinib, a selective Bruton tyrosine kinase inhibitor, in Chinese patients with relapsed/refractory B‐cell malignancies. Br J Haematol. 2022;198(1):62‐72. https://doi.org/10.1111/bjh.18162

Blombery P, Thompson ER, Lew TE, et al. Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross‐resistance. Blood Adv. 2022;6(20):5589‐5592. https://doi.org/10.1182/bloodadvances.2022008325

Wang S, Mondal S, Zhao C, et al. Noncovalent inhibitors reveal BTK gatekeeper and auto‐inhibitory residues that control its transforming activity. JCI Insight. 2019;4(12):e127566. https://doi.org/10.1172/jci.insight.127566

Tatarczuch M, Waltham M, Shortt J, et al. Molecular associations of response to the new generation BTK inhibitor zanubrutinib in marginal zone lymphoma. Blood Adv. 2023;7(14):3531‐3539. https://doi.org/10.1182/bloodadvances.2022009412

Schmid VK, Hobeika E. B cell receptor signaling and associated pathways in the pathogenesis of chronic lymphocytic leukemia. Front Oncol. 2024;14:1339620. https://doi.org/10.3389/fonc.2024.1339620

Yang X, Yang X, Cui X, et al. Abstract 664: BGB‐10188, a highly selective PI3Kδ inhibitor with improved safety profile and superior anti‐tumor activities in vivo. Cancer Res. 2020;80(suppl 16):664. https://doi.org/10.1158/1538‐7445.AM2020‐664

Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997‐1007. https://doi.org/10.1056/NEJMoa1315226

Danilov AV, Muir A, Melgar I, et al. A phase II trial of acalabrutinib in combination with PI3Kδ inhibitor umbralisib and the anti‐CD20 antibody ublituximab (AU2) in patients with previously untreated mantle cell lymphoma (MCL). Blood. 2022;140(suppl 1):3633‐3634. https://doi.org/10.1182/blood‐2022‐159805

Strazza M, Adam K, Lerrer S, et al. SHP2 targets ITK downstream of PD‐1 to inhibit T cell function. Inflammation. 2021;44(4):1529‐1539. https://doi.org/10.1007/s10753‐021‐01437‐8

Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1‐selective pressure in T lymphocytes. Blood. 2013;122(15):2539‐2549. https://doi.org/10.1182/blood‐2013‐06‐507947

Sagiv‐Barfi I, Kohrt HEK, Czerwinski DK, Ng PP, Chang BY, Levy R. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci USA. 2015;112(9):E966‐E972. https://doi.org/10.1073/pnas.1500712112

Long M, Beckwith K, Do P, et al. Ibrutinib treatment improves T cell number and function in CLL patients. J Clin Invest. 2017;127(8):3052‐3064. https://doi.org/10.1172/JCI89756

O’Brien SM, Brown JR, Byrd JC, et al. Monitoring and managing BTK inhibitor treatment‐related adverse events in clinical practice. Front Oncol. 2021;11:720704. https://doi.org/10.3389/fonc.2021.720704

Wirsching H.‐G, Weller M, Balabanov S, Roth P. Targeted therapies and immune checkpoint inhibitors in primary CNS lymphoma. Cancers. 2021;13(12):3073. https://doi.org/10.3390/cancers13123073

Tam C, Munoz J, Cull G, et al. Zanubrutinib, alone and in combination with tislelizumab, for the treatment of richter transformation of chronic lymphocytic leukemia. HemaSphere. 2023;7(4):e870. https://doi.org/10.1097/HS9.0000000000000870

Lyu J, Ma X, Huang R, et al. Biomarker analysis of zanubrutinib and tislelizumab combination therapy in patients with relapsed/refractory B‐cell malignancies. Blood. 2022;140(suppl 1):3521‐3522. https://doi.org/10.1182/blood‐2022‐168474

Diepstraten ST, Anderson MA, Czabotar PE, Lessene G, Strasser A, Kelly GL. The manipulation of apoptosis for cancer therapy using BH3‐mimetic drugs. Nat Rev Cancer. 2022;22(1):45‐64. https://doi.org/10.1038/s41568‐021‐00407‐4

Kuo H.‐P, Ezell SA, Schweighofer KJ, et al. Combination of ibrutinib and ABT‐199 in diffuse large B‐cell lymphoma and follicular lymphoma. Mol Cancer Therapeut. 2017;16(7):1246‐1256. https://doi.org/10.1158/1535‐7163.MCT‐16‐0555

Lu P, Wang S, Franzen CA, et al. Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication. Blood Cancer J. 2021;11(2):39. https://doi.org/10.1038/s41408‐021‐00429‐z

Zhang J, Lu X, Li J, Miao Y. Combining BTK inhibitors with BCL2 inhibitors for treating chronic lymphocytic leukemia and mantle cell lymphoma. Biomark Res. 2022;10(1):17. https://doi.org/10.1186/s40364‐022‐00357‐5

Bertram K, Leary PJ, Boudesco C, et al. Inhibitors of Bcl‐2 and Bruton’s tyrosine kinase synergize to abrogate diffuse large B‐cell lymphoma growth in vitro and in orthotopic xenotransplantation models. Leukemia. 2022;36(4):1035‐1047. https://doi.org/10.1038/s41375‐021‐01470‐4

Hu N, Guo Y, Xue H, et al. Abstract 3077: preclinical characterization of BGB‐11417, a potent and selective Bcl‐2 inhibitor with superior antitumor activities in haematological tumor models. Cancer Res. 2020;80(suppl 16):3077. https://doi.org/10.1158/1538‐7445.AM2020‐3077

Polyak MJ, Li H, Shariat N, Deans JP. CD20 homo‐oligomers physically associate with the B cell antigen receptor. J Biol Chem. 2008;283(27):18545‐18552. https://doi.org/10.1074/jbc.M800784200

Da Roit F, Engelberts PJ, Taylor RP, et al. Ibrutinib interferes with the cell‐mediated anti‐tumor activities of therapeutic CD20 antibodies: implications for combination therapy. Haematologica. 2015;100(1):77‐86. https://doi.org/10.3324/haematol.2014.107011

Kohrt HE, Sagiv‐Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab‐dependent NK cell–mediated cytotoxicity. Blood. 2014;123(12):1957‐1960. https://doi.org/10.1182/blood‐2014‐01‐547869

Khurana D, Arneson LN, Schoon RA, Dick CJ, Leibson PJ. Differential regulation of human NK cell‐mediated cytotoxicity by the tyrosine kinase itk. J Immunol. 2007;178(6):3575‐3582. https://doi.org/10.4049/jimmunol.178.6.3575

Pavlasova G, Mraz M. The regulation and function of CD20: an “enigma” of B‐cell biology and targeted therapy. Haematologica. 2020;105(6):1494‐1506. https://doi.org/10.3324/haematol.2019.243543

Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517‐2528. https://doi.org/10.1056/NEJMoa1812836

Burger JA, Sivina M, Jain N, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133(10):1011‐1019. https://doi.org/10.1182/blood‐2018‐10‐879429

Moreno C, Greil R, Demirkan F, 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(1):43‐56. https://doi.org/10.1016/S1470‐2045(18)30788‐5

Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4‐year follow‐up of the ELEVATE‐TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment‐naïve chronic lymphocytic leukemia. Leukemia. 2020;36(4):1171‐1175. https://doi.org/10.1038/s41375‐021‐01485‐x

Tam CS, Quach H, Nicol A, et al. Zanubrutinib (BGB‐3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. Blood Adv. 2020;4(19):4802‐4811. https://doi.org/10.1182/bloodadvances.2020002183

Buske C, Jurczak W, Salem J.‐E, Dimopoulos MA. Managing Waldenström’s macroglobulinemia with BTK inhibitors. Leukemia. 2023;37(1):35‐46. https://doi.org/10.1038/s41375‐022‐01732‐9

Keam SJ. Pirtobrutinib: first approval. Drugs. 2023;83(6):547‐553. https://doi.org/10.1007/s40265‐023‐01860‐1

Gomez EB, Ebata K, Randeria HS, et al. Pirtobrutinib preclinical characterization: a highly selective, non‐covalent (reversible) BTK inhibitor. Blood. 2023;142(1):62‐72. https://doi.org/10.1182/blood.2022018674

Naeem A, Utro F, Wang Q, et al. Pirtobrutinib targets BTK C481S in ibrutinib‐resistant CLL but second‐site BTK mutations lead to resistance. Blood Adv. 2023;7(9):1929‐1943. https://doi.org/10.1182/bloodadvances.2022008447

Woyach JA, Flinn IW, Awan FT, et al. Efficacy and safety of nemtabrutinib, a wild‐type and C481S‐mutated Bruton tyrosine kinase inhibitor for B‐cell malignancies: updated analysis of the open‐label phase 1/2 dose‐expansion bellwave‐001 study. Blood. 2022;140(1):7004‐7006. https://doi.org/10.1182/blood‐2022‐163596

Liu Z, Hu M, Yang Y, et al. An overview of PROTACs: a promising drug discovery paradigm. Mol Biomed. 2022;3(1):46. https://doi.org/10.1186/s43556‐022‐00112‐0

Hughes SJ, Testa A, Thompson N, Churcher I. The rise and rise of protein degradation: opportunities and challenges ahead. Drug Discov Today. 2021;26(12):2889‐2897. https://doi.org/10.1016/j.drudis.2021.08.006

Buhimschi AD, Armstrong HA, Toure M, et al. Targeting the C481S ibrutinib‐resistance mutation in bruton’s tyrosine kinase using PROTAC‐mediated degradation. Biochemistry. 2018;57(26):3564‐3575. https://doi.org/10.1021/acs.biochem.8b00391

Sun Y, Zhao X, Ding N, et al. PROTAC‐induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib‐resistant B‐cell malignancies. Cell Res. 2018;28(7):779‐781. https://doi.org/10.1038/s41422‐018‐0055‐1

Sun Y, Ding N, Song Y, et al. Degradation of Bruton’s tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib‐resistant non‐Hodgkin lymphomas. Leukemia. 2019;33(8):2105‐2110. https://doi.org/10.1038/s41375‐019‐0440‐x

Zhao Y, Shu Y, Lin J, et al. Discovery of novel BTK PROTACs for B‐Cell lymphomas. Eur J Med Chem. 2021;225:113820. https://doi.org/10.1016/j.ejmech.2021.113820

Lim YS, Yoo S.‐M, Patil V, et al. Orally bioavailable BTK PROTAC active against wild‐type and C481 mutant BTKs in human lymphoma CDX mouse models. Blood Adv. 2023;7(1):92‐105. https://doi.org/10.1182/bloodadvances.2022008121

Robbins DW, Noviski M, Rountree R, et al. Nx‐5948, a selective degrader of BTK with activity in preclinical models of hematologic and brain malignancies. Blood. 2021;138(suppl 1):2251. https://doi.org/10.1182/blood‐2021‐147473

Mato AR, Wierda WG, Ai WZ, et al. NX‐2127‐001, a first‐in‐human trial of NX‐2127, a bruton’s tyrosine kinase‐targeted protein degrader, in patients with relapsed or refractory chronic lymphocytic leukemia and B‐cell malignancies. Blood. 2022;140(suppl 1):2329‐2332. https://doi.org/10.1182/blood‐2022‐164772

Fiskus WC, Das K, Mill CP, et al. Bruton’s tyrosine kinase (BTK) degrader nx‐2127 exhibits lethal activity and synergy with venetoclax and BET protein inhibitor against MCL cells sensitive or resistant to covalent BTK inhibitors. Blood. 2022;140(suppl 1):5980‐5981. https://doi.org/10.1182/blood‐2022‐168483

Noviski MA, Brathaban N, Mukerji R, et al. Abstract 2850: NX‐5948 promotes selective, sub‐nanomolar degradation of inhibitor‐resistant BTK mutants. Cancer Res. 2023;83(7_suppl ment):2850. https://doi.org/10.1158/1538‐7445.AM2023‐2850

Guo Y, Liu Y, Hu N, et al. Discovery of zanubrutinib (BGB‐3111), a novel, potent, and selective covalent inhibitor of bruton’s tyrosine kinase. J Med Chem. 2019;62(17):7923‐7940. https://doi.org/10.1021/acs.jmedchem.9b00687

You I, Erickson EC, Donovan KA, et al. Discovery of an AKT degrader with prolonged inhibition of downstream signaling. Cell Chem Biol. 2020;27(1):66‐73.e7. https://doi.org/10.1016/j.chembiol.2019.11.014

Zhu C.‐L, Luo X, Tian T, et al. Structure‐based rational design enables efficient discovery of a new selective and potent AKT PROTAC degrader. Eur J Med Chem. 2022;238:114459. https://doi.org/10.1016/j.ejmech.2022.114459