Short NJ, Rytting ME, Cortes JE. Acute myeloid leukaemia. Lancet. 2018;392:593–606.
Google Scholar
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.
Google Scholar
Ikhtiar F, Jamal A, Bokhari SMSM. Deciphering and targeting oncogenic pathways through integrated approaches and amino acid metabolism in hematologic malignancies. Discov Oncol. 2025;16:1687.
Google Scholar
Henley MJ, Koehler AN. Advances in targeting ‘undruggable’ transcription factors with small molecules. Nat Rev Drug Discov. 2021;20:669–88.
Google Scholar
Jung H, Lee Y. Targeting the undruggable: recent progress in PROTAC-induced transcription factor degradation. Cancers. 2025;17:1871.
Google Scholar
Cui H, Stilgenbauer M, Koehler AN. Small-molecule approaches to target transcription factors. Annu Rev Cancer Biol. 2024;8:395–415.
Google Scholar
Park J, Cho J, Song EJ. Ubiquitin–proteasome system (UPS) as a target for anticancer treatment. Arch Pharm Res. 2020;43:1144–61.
Google Scholar
Dagar G, Kumar R, Yadav KK, Singh M, Pandita TK. Ubiquitination and deubiquitination: Implications on cancer therapy. Biochim Biophys Acta Gene Regul Mechan. 2023;1866:194979.
Google Scholar
Zhang X, Linder S, Bazzaro M. Drug development targeting the ubiquitin–proteasome system (UPS) for the treatment of human cancers. Cancers. 2020;12:902.
Google Scholar
Abbas R, Larisch S. Killing by degradation: regulation of apoptosis by the ubiquitin-proteasome-system. Cells. 2021;10:3465.
Google Scholar
Davies F, Rifkin R, Costello C, Morgan G, Usmani S, Abonour R, et al. Real-world comparative effectiveness of triplets containing bortezomib (B), carfilzomib (C), daratumumab (D), or ixazomib (I) in relapsed/refractory multiple myeloma (RRMM) in the US. Ann Hematol. 2021;100:2325–37.
Google Scholar
Irimia R, Badelita SN, Barbu S, Zidaru L, Carlan IL, Coriu D. The efficacy of carfilzomib treatment in bortezomib-refractory patients—real life experience in a tertiary Romanian hospital. J Clin Med. 2024;13:2171.
Google Scholar
Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, et al. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012;158:739–48.
Google Scholar
Zengerle M, Chan K-H, Ciulli A. Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem Biol. 2015;10:1770–7.
Google Scholar
Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, et al. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015;348:1376–81.
Google Scholar
Zhou B, Hu J, Xu F, Chen Z, Bai L, Fernandez-Salas E, et al. Discovery of a small-molecule degrader of bromodomain and extra-terminal (BET) proteins with picomolar cellular potencies and capable of achieving tumor regression. J Med Chem. 2018;61:462–81.
Google Scholar
Nabet B, Roberts JM, Buckley DL, Paulk J, Dastjerdi S, Yang A, et al. The dTAG system for immediate and target-specific protein degradation. Nat Chem Biol. 2018;14:431–41.
Google Scholar
Liu L, Yang C, Lavayen BP, Tishko RJ, Larochelle J, Candelario-Jalil E. Targeted BRD4 protein degradation by dBET1 ameliorates acute ischemic brain injury and improves functional outcomes associated with reduced neuroinflammation and oxidative stress and preservation of blood–brain barrier integrity. J Neuroinflam. 2022;19:168.
Google Scholar
Lu L, Chen Z, Lin X, Tian L, Su Q, An P, et al. Inhibition of BRD4 suppresses the malignancy of breast cancer cells via regulation of Snail. Cell Death Differ. 2020;27:255–68.
Google Scholar
Zhang H, Li G, Zhang Y, Shi J, Yan B, Tang H, et al. Targeting BET proteins with a PROTAC molecule elicits potent anticancer activity in HCC cells. Front Oncol. 2020;9. https://doi.org/10.3389/fonc.2019.01471.
Ren J, Huang Y, Wang J, Xu S, Wang L, Yan Q, et al. Discovery of TQ-3959 as a potent and orally bioavailable BTK PROTAC degrader incorporating a novel benzisoxazole-based CRBN ligand for the treatment of B-cell malignancies. J Med Chem. 2025;68:15960–79.
Google Scholar
Lee J, Sung KW, Bae E-J, Yoon D, Kim D, Lee JS, et al. Targeted degradation of α-synuclein aggregates in Parkinson’s disease using the AUTOTAC technology. Mol Neurodegener. 2023;18:41.
Google Scholar
Park DY, Kim HY, Cho EH, Choi H, Park D, Lee GE, et al. Targeted degradation of pathogenic TDP-43 proteins in amyotrophic lateral sclerosis using the AUTOTAC platform. 2025. https://doi.org/10.1101/2025.08.31.673396.
Ishikawa C, Barreyro L, Sampson AM, Hueneman KM, Choi K, Philbrook SY, et al. Ubiquitin-conjugating enzyme UBE2N modulates proteostasis in immunoproteasome-positive acute myeloid leukemia. J Clin Invest. 2025;135. https://doi.org/10.1172/JCI184665.
Kim D, Nam HJ, Baek SH. Ubiquitination of transcription factors in cancer: unveiling therapeutic potential. Mol Oncol. 2025;19:2174–95.
Google Scholar
Yang L, Li JN. E3 ubiquitin ligase neural precursor cell-expressed developmentally downregulated gene 4 motivates FOXA1 ubiquitination and restrains proliferation of diffuse large B-cell lymphoma cells via the Wnt/β-Catenin pathway. Cell Biol Int. 2023;47:1688–701.
Google Scholar
Lei H, Wang J, Hu J, Zhu Q, Wu Y. Deubiquitinases in hematological malignancies. Biomark Res. 2021;9:66.
Google Scholar
Fhu CW, Ali A. Dysregulation of the ubiquitin proteasome system in human malignancies: a window for therapeutic intervention. Cancers. 2021;13:1513.
Google Scholar
Sampson C, Wang Q, Otkur W, Zhao H, Lu Y, Liu X, et al. The roles of E3 ubiquitin ligases in cancer progression and targeted therapy. Clin Transl Med. 2023;13. https://doi.org/10.1002/ctm2.1204.
Dong Y, Tu R, Liu H, Qing G. Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat. Signal Transduct Target Ther. 2020;5:124.
Google Scholar
Xiong X, Chen X, Shao S, Cui D, Qu R, Wang B, et al. DEPTOR suppresses lymphomagenesis by promoting EGFR degradation via HUWE1 E3 ligase. Cell Death Differ. 2025;32:1820–32.
Google Scholar
Close V, Close W, Kugler SJ, Reichenzeller M, Yosifov DY, Bloehdorn J, et al. FBXW7 mutations reduce binding of NOTCH1, leading to cleaved NOTCH1 accumulation and target gene activation in CLL. Blood. 2019;133:830–9.
Google Scholar
Sharma A, Khan H, Singh T, Grewal A, Najda A, Kawecka-Radomska M, et al. Pharmacological modulation of ubiquitin-proteasome pathways in oncogenic signaling. Int J Mol Sci. 2021;22:11971.
Google Scholar
Liu F, Chen J, Li K, Li H, Zhu Y, Zhai Y, et al. Ubiquitination and deubiquitination in cancer: from mechanisms to novel therapeutic approaches. Mol Cancer. 2024;23:148.
Google Scholar
Manasanch EE, Orlowski RZ. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol. 2017;14:417–33.
Google Scholar
Sedlacek J. Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma. Clin Exp Med. 2025;25:176.
Google Scholar
Lam K, Kim YJ, Ong CM, Liu A, Chua B, Zhou J-H, et al. Disrupting autophagy sensitizes human acute myeloid leukemia cells to proteasome inhibition by disrupting protein homeostasis. Blood. 2023;142:2805.
Google Scholar
Ri M. Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma. Int J Hematol. 2016;104:273–80.
Google Scholar
Aliabadi F, Sohrabi B, Mostafavi E, Pazoki-Toroudi H, Webster TJ. Ubiquitin–proteasome system and the role of its inhibitors in cancer therapy. Open Biol. 2021;11. https://doi.org/10.1098/rsob.200390.
Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009;458:732–6.
Google Scholar
Soucy TA, Smith PG, Rolfe M. Targeting NEDD8-activated Cullin-RING ligases for the treatment of cancer. Clin Cancer Res. 2009;15:3912–6.
Google Scholar
Hyer ML, Milhollen MA, Ciavarri J, Fleming P, Traore T, Sappal D, et al. A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment. Nat Med. 2018;24:186–93.
Google Scholar
Pakjoo M, Ahmadi SE, Zahedi M, Jaafari N, Khademi R, Amini A, et al. Interplay between proteasome inhibitors and NF-κB pathway in leukemia and lymphoma: a comprehensive review on challenges ahead of proteasome inhibitors. Cell Commun Signal. 2024;22:105.
Google Scholar
Anaya YA, Barragan M, Bracho RP, Shaham SH, Bandyopadhyay D, George E, et al. Proteolysis-targeting chimeras in cancer therapy: Targeted protein degradation for next-generation treatment. Cancer. 2025;131. https://doi.org/10.1002/cncr.70132.
Asadi S, Taheri-Torbati M, Kesharwani P, Sahebkar A. Lysosome-mediated targeted protein degradation: emerging chimeric platforms for extracellular and intracellular therapeutics. Drug Dev Res. 2025;86. https://doi.org/10.1002/ddr.70197.
Alam MM, Wasim S, Lee S-Y. Emerging concepts of targeted protein degrader technologies via lysosomal pathways. Int J Mol Sci. 2025;26:5582.
Google Scholar
Li X, Pu W, Zheng Q, Ai M, Chen S, Peng Y. Proteolysis-targeting chimeras (PROTACs) in cancer therapy. Mol Cancer. 2022;21:99.
Google Scholar
Girardini M, Maniaci C, Hughes SJ, Testa A, Ciulli A. Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs. Bioorg Med Chem. 2019;27:2466–79.
Google Scholar
Miletić N, Weckesser J, Mosler T, Rathore R, Hoffmann ME, Gehrtz P, et al. Workflow for E3 ligase ligand validation for PROTAC development. ACS Chem Biol. 2025;20:507–21.
Google Scholar
Lee J, Lee Y, Jung YM, Park JH, Yoo HS, Park J. Discovery of E3 ligase ligands for target protein degradation. Molecules. 2022;27:6515.
Google Scholar
Li X, Song Y. Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy. J Hematol Oncol. 2020;13:50.
Google Scholar
Kumar H, Sobhia ME. Interplay of PROTAC complex dynamics for undruggable targets: insights into ternary complex behavior and linker design. ACS Med Chem Lett. 2024;15:1306–18.
Google Scholar
Kudo G, Hirao T, Harada R, Shigeta Y, Hirokawa T, Yoshino R. Construction of PROTAC-mediated ternary complex structure distribution profiles using extensive conformational search. J Chem Inf Model. 2025;65:6939–48.
Google Scholar
Li Y, Zhang X, Xie J, Meng D, Liu M, Chang Y, et al. Analyzing the linker structure of PROTACs throughout the induction process: computational insights. J Med Chem. 2025;68:3420–32.
Google Scholar
Surka C, Jin L, Mbong N, Lu C-C, Jang IS, Rychak E, et al. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells. Blood. 2021;137:661–77.
Google Scholar
Yoon H, Rutter JC, Li Y-D, Ebert BL. Induced protein degradation for therapeutics: past, present, and future. J Clin Invest. 2024;134. https://doi.org/10.1172/JCI175265.
Barrio S, Munawar U, Zhu YX, Giesen N, Shi C-X, Viá MD, et al. IKZF1/3 and CRL4 CRBN E3 ubiquitin ligase mutations and resistance to immunomodulatory drugs in multiple myeloma. Haematologica. 2020;105:e237–e241.
Google Scholar
Wang B, Li M, Cao D, Sun Q, Yu W, Ma J, et al. Lys-63-specific deubiquitinase BRCC36 enhances the sensitivity of multiple myeloma cells to lenalidomide by inhibiting lysosomal degradation of cereblon. Cell Mol Life Sci. 2024;81:349.
Google Scholar
Costacurta M, He J, Thompson PE, Shortt J. Molecular mechanisms of cereblon-interacting small molecules in multiple myeloma therapy. J Pers Med. 2021;11:1185.
Google Scholar
Bjorklund CC, Kang J, Amatangelo M, Polonskaia A, Katz M, Chiu H, et al. Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN. Leukemia. 2020;34:1197–201.
Google Scholar
Hartley-Brown MA, Mo CC, Nadeem O, Midha S, Laubach JP, Richardson PG. Mezigdomide—a novel cereblon E3 ligase modulator under investigation in relapsed/refractory multiple myeloma. Cancers. 2024;16:1166.
Google Scholar
Lopez-Girona A, Havens CG, Lu G, Rychak E, Mendy D, Gaffney B, et al. CC-92480 is a novel cereblon E3 ligase modulator with enhanced tumoricidal and immunomodulatory activity against sensitive and resistant multiple myeloma cells. Blood. 2019;134:1812.
Google Scholar
Hansen JD, Correa M, Nagy MA, Alexander M, Plantevin V, Grant V, et al. Discovery of CRBN E3 ligase modulator CC-92480 for the treatment of relapsed and refractory multiple myeloma. J Med Chem. 2020;63:6648–76.
Google Scholar
Liu Y, Mo CC, Hartley-Brown MA, Sperling AS, Midha S, Yee AJ, et al. Targeting Ikaros and Aiolos: reviewing novel protein degraders for the treatment of multiple myeloma, with a focus on iberdomide and mezigdomide. Expert Rev Hematol. 2024;17:445–65.
Google Scholar
Watson ER, Novick S, Matyskiela ME, Chamberlain PP H, de la Peña A, Zhu J, et al. Molecular glue CELMoD compounds are regulators of cereblon conformation. Science. 2022;378:549–53.
Google Scholar
Banik SM, Pedram K, Wisnovsky S, Ahn G, Riley NM, Bertozzi CR. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature. 2020;584:291–7.
Google Scholar
Ahn G, Banik SM, Miller CL, Riley NM, Cochran JR, Bertozzi CR. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat Chem Biol. 2021;17:937–46.
Google Scholar
Takahashi D, Moriyama J, Nakamura T, Miki E, Takahashi E, Sato A, et al. AUTACs: cargo-specific degraders using selective autophagy. Mol Cell. 2019;76:797–810.e10.
Google Scholar
Ahn G, Riley NM, Kamber RA, Wisnovsky S, Moncayo von Hase S, Bassik MC, et al. Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras. Science. 2023;382. https://doi.org/10.1126/science.adf6249.
Xing Y, Li J, Wang L, Zhu Z, Yan J, Liu Y, et al. A Bifunctional lysosome-targeting chimera nanoplatform for tumor-selective protein degradation and enhanced cancer immunotherapy. Adv Mater. 2025;37. https://doi.org/10.1002/adma.202417942.
Yu J, Li H, Fang T, Yun C, Liu X, Xu J, et al. Harnessing the lysosomal sorting signals of the cation-independent Mannose-6-phosphate receptor for targeted degradation of membrane proteins. J Am Chem Soc. 2023;145:19107–19.
Google Scholar
Mamun MAA, Bakunts AG, Chernorudskiy AL. Targeted degradation of extracellular proteins: state of the art and diversity of degrader designs. J Hematol Oncol. 2025;18:52.
Google Scholar
Li Y, Yang Y, Zhang R, Ge R, Xie S. Targeted degradation of membrane and extracellular proteins with LYTACs. Acta Pharm Sin. 2025;46:1–7.
Google Scholar
Ji CH, Kim HY, Lee MJ, Heo AJ, Park DY, Lim S, et al. The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system. Nat Commun. 2022;13:904.
Google Scholar
Wang Y, Yang L, Yan C, Du Y, Li T, Yang W, et al. Supramolecular artificial Nano-AUTACs enable tumor-specific metabolism protein degradation for synergistic immunotherapy. Sci Adv. 2024;10. https://doi.org/10.1126/sciadv.adn8079.
Takahashi D, Ora T, Sasaki S, Ishii N, Tanaka T, Matsuda T, et al. Second-generation AUTACs for targeted autophagic degradation. J Med Chem. 2023;66:12342–72.
Google Scholar
Paudel RR, Lu D, Roy Chowdhury S, Monroy EY, Wang J. Targeted protein degradation via lysosomes. Biochemistry. 2023;62:564–79.
Google Scholar
Mikitiuk M, Barczyński J, Bielski P, Arciniega M, Tyrcha U, Hec A, et al. IGF2 peptide-based LYTACs for targeted degradation of extracellular and transmembrane proteins. Molecules. 2023;28:7519.
Google Scholar
Piya S, Mu H, Bhattacharya S, Lorenzi PL, Davis RE, McQueen T, et al. BETP degradation simultaneously targets acute myelogenous leukemic stem cells and the microenvironment. J Clin Investig. 2019;129:1878–94.
Google Scholar
Sun B, Fiskus W, Qian Y, Rajapakshe K, Raina K, Coleman KG, et al. BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells. Leukemia. 2018;32:343–52.
Google Scholar
Zhang K, Gao L, Wang J, Chu X, Zhang Z, Zhang Y, et al. A novel BRD family PROTAC inhibitor dBET1 exerts great anti-cancer effects by targeting c-MYC in acute myeloid leukemia cells. Pathol Oncol Res. 2022;28. https://doi.org/10.3389/pore.2022.1610447.
Ma L, Wang J, Zhang Y, Fang F, Ling J, Chu X, et al. BRD4 PROTAC degrader MZ1 exerts anticancer effects in acute myeloid leukemia by targeting c-Myc and ANP32B genes. Cancer Biol Ther. 2022;23:1–15.
Google Scholar
Saenz DT, Fiskus W, Qian Y, Manshouri T, Rajapakshe K, Raina K, et al. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia. 2017;31:1951–61.
Google Scholar
Piya S, Bhattacharya S, Mu H, Lorenzi PL, McQueen T, Davis ER, et al. BRD4 proteolysis targeting chimera (PROTAC) ARV-825, causes sustained degradation of BRD4 and modulation of chemokine receptors, cell adhesion and metabolic targets in leukemia resulting in profound anti-leukemic effects. Blood. 2016;128:748–748.
Google Scholar
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.
Google Scholar
Tam C, Thompson PA. BTK inhibitors in CLL: second-generation drugs and beyond. Blood Adv. 2024;8:2300–9.
Google Scholar
Shirley M. Bruton tyrosine kinase inhibitors in B-cell malignancies: their use and differential features. Target Oncol. 2022;17:69–84.
Google Scholar
Bravo-Gonzalez A, Alasfour M, Soong D, Noy J, Pongas G. Advances in targeted therapy: addressing resistance to BTK inhibition in B-cell lymphoid malignancies. Cancers. 2024;16:3434.
Google Scholar
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.
Google Scholar
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.
Google Scholar
Montoya S, Bourcier J, Noviski M, Lu H, Thompson MC, Chirino A, et al. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science. 2024;383. https://doi.org/10.1126/science.adi5798.
Danilov A, Tees MT, Patel K, Wierda WG, Patel M, Flinn IW, et al. A first-in-human phase 1 trial of NX-2127, a first-in-class Bruton’s tyrosine kinase (BTK) dual-targeted protein degrader with immunomodulatory activity, in patients with relapsed/refractory B cell malignancies. Blood. 2023;142:4463.
Google Scholar
Searle E, Forconi F, Linton K, Danilov A, McKay P, Lewis D, et al. Initial findings from a first-in-human phase 1a/b trial of NX-5948, a selective Bruton’s tyrosine kinase (BTK) degrader, in patients with relapsed/refractory B cell malignancies. Blood. 2023;142:4473.
Google Scholar
Seymour JF, Cheah CY, Parrondo R, Thompson MC, Stevens DA, Lasica M, et al. First results from a phase 1, first-in-human study of the Bruton’s tyrosine kinase (BTK) degrader Bgb-16673 in patients (Pts) with relapsed or refractory (R/R) B-cell malignancies (BGB-16673-101). Blood. 2023;142:4401.
Google Scholar
Shah NN, Omer Z, Collins GP, Forconi F, Danilov A, Byrd JC, et al. Efficacy and safety of the Bruton’s tyrosine kinase (BTK) degrader NX-5948 in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): updated results from an ongoing phase 1a/b study. Blood. 2024;144:884.
Google Scholar
Zhu H-Q, Gao F-H. Regulatory molecules and corresponding processes of BCR-ABL protein degradation. J Cancer. 2019;10:2488–2500.
Google Scholar
Burslem GM, Schultz AR, Bondeson DP, Eide CA, Savage Stevens SL, Druker BJ, et al. Targeting BCR-ABL1 in chronic myeloid leukemia by PROTAC-mediated targeted protein degradation. Cancer Res. 2019;79:4744–53.
Google Scholar
Liu H, Ding X, Liu L, Mi Q, Zhao Q, Shao Y, et al. Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation. Eur J Med Chem. 2021;223:113645.
Google Scholar
Shibata N, Miyamoto N, Nagai K, Shimokawa K, Sameshima T, Ohoka N, et al. Development of protein degradation inducers of oncogenic BCR – ABL protein by conjugation of ABL kinase inhibitors and IAP ligands. Cancer Sci. 2017;108:1657–66.
Google Scholar
Yang Y, Gao H, Sun X, Sun Y, Qiu Y, Weng Q, et al. Global PROTAC toolbox for degrading BCR–ABL overcomes drug-resistant mutants and adverse effects. J Med Chem. 2020;63:8567–83.
Google Scholar
Liu H, Mi Q, Ding X, Lin C, Liu L, Ren C, et al. Discovery and characterization of novel potent BCR-ABL degraders by conjugating allosteric inhibitor. Eur J Med Chem. 2022;244:114810.
Google Scholar
Jiang L, Wang Y, Li Q, Tu Z, Zhu S, Tu S, et al. Design, synthesis, and biological evaluation of Bcr-Abl PROTACs to overcome T315I mutation. Acta Pharm Sin B. 2021;11:1315–28.
Google Scholar
Elgehama A, Wang Y, Yu Y, Zhou L, Chen Z, Wang L, et al. Targeting the PTP1B-Bcr-Abl1 interaction for the degradation of T315I mutant Bcr-Abl1 in chronic myeloid leukemia. Cancer Sci. 2023;114:247–58.
Google Scholar
Brand M, Jiang B, Bauer S, Donovan KA, Liang Y, Wang ES, et al. Homolog-selective degradation as a strategy to probe the function of CDK6 in AML. Cell Chem Biol. 2019;26:300–6.e9.
De Dominici M, Porazzi P, Xiao Y, Chao A, Tang H-Y, Kumar G, et al. Selective inhibition of Ph-positive ALL cell growth through kinase-dependent and -independent effects by CDK6-specific PROTACs. Blood. 2020;135:1560–73.
Google Scholar
Su S, Yang Z, Gao H, Yang H, Zhu S, An Z, et al. Potent and preferential degradation of CDK6 via proteolysis targeting chimera degraders. J Med Chem. 2019;62:7575–82.
Google Scholar
Rana S, Mallareddy JR, Singh S, Boghean L, Natarajan A. Inhibitors, PROTACs and molecular glues as diverse therapeutic modalities to target cyclin-dependent kinase. Cancers. 2021;13:5506.
Google Scholar
Steinebach C, Ng YLD, Sosič I, Lee C-S, Chen S, Lindner S, et al. Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders. Chem Sci. 2020;11:3474–86.
Google Scholar
Marei HE, Bedair K, Hasan A, Al-Mansoori L, Gaiba A, Morrione A, et al. Targeting CDKs in cancer therapy: advances in PROTACs and molecular glues. NPJ Precis Oncol. 2025;9:204.
Google Scholar
Robb CM, Contreras JI, Kour S, Taylor MA, Abid M, Sonawane YA, et al. Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC). Chem Commun. 2017;53:7577–80.
Google Scholar
Xiao L, Liu Y, Chen H, Shen L. Targeting CDK9 with selective inhibitors or degraders in tumor therapy: an overview of recent developments. Cancer Biol Ther. 2023;24. https://doi.org/10.1080/15384047.2023.2219470.
Reznickova E, Krajčovičová S, Peřina M, Kovalová M, Soural M, Krystof V. Modulation of FLT3-ITD and CDK9 in acute myeloid leukaemia cells by novel proteolysis targeting chimera (PROTAC). SSRN Electronic J. 2022. https://doi.org/10.2139/ssrn.4185391.
Koirala M, DiPaola M. Targeting CDK9 in cancer: an integrated approach of combining in silico screening with experimental validation for novel degraders. Curr Issues Mol Biol. 2024;46:1713–30.
Google Scholar
Bai L, Zhou H, Xu R, Zhao Y, Chinnaswamy K, McEachern D, et al. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell. 2019;36:498–511.e17.
Google Scholar
Li S, Wang X, Huang J, Cao X, Liu Y, Bai S, et al. Decoy-PROTAC for specific degradation of “Undruggable” STAT3 transcription factor. Cell Death Dis. 2025;16:197.
Google Scholar
Kelm JM, Pandey DS, Malin E, Kansou H, Arora S, Kumar R, et al. PROTAC’ing oncoproteins: targeted protein degradation for cancer therapy. Mol Cancer. 2023;22:62.
Google Scholar
Wang J, Rong Q, Ye L, Fang B, Zhao Y, Sun Y, et al. Discovery of a novel orally bioavailable FLT3-PROTAC degrader for efficient treatment of acute myeloid leukemia and overcoming resistance of FLT3 inhibitors. J Med Chem. 2024;67:7197–223.
Google Scholar
He Y, Koch R, Budamagunta V, Zhang P, Zhang X, Khan S, et al. DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas. J Hematol Oncol. 2020;13:95.
Google Scholar
Khan S, Cao L, Wiegand J, Zhang P, Zajac-Kaye M, Kaye FJ, et al. PROTAC-mediated dual degradation of BCL-xL and BCL-2 is a highly effective therapeutic strategy in small-cell lung cancer. 2024. https://doi.org/10.1101/2024.02.27.582353.
Lim YS, Yoo S-M, Patil V, Kim HW, Kim H-H, Suh B, et al. Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models. Blood Adv. 2023;7:92–105.
Google Scholar
Kelly A, Robbins DW, Tan M, Tenn-McClellan A, McIntosh J, Wu J, et al. Targeted protein degradation of BTK as a unique therapeutic approach for B cell malignancies. Blood. 2019;134:3805.
Google Scholar
Robbins DW, Noviski MA, Tan YS, Konst ZA, Kelly A, Auger P, et al. Discovery and preclinical pharmacology of NX-2127, an orally bioavailable degrader of Bruton’s tyrosine kinase with immunomodulatory activity for the treatment of patients with B cell malignancies. J Med Chem. 2024;67:2321–36.
Google Scholar
Piya S, Yang Y, Bhattacharya S, Sharma P, Ma H, Mu H, et al. Targeting the NOTCH1-MYC-CD44 axis in leukemia-initiating cells in T-ALL. Leukemia. 2022;36:1261–73.
Google Scholar
Dickinson M, Briones J, Herrera AF, González-Barca E, Ghosh N, Cordoba R, et al. Phase 1b study of the BET protein inhibitor RO6870810 with venetoclax and rituximab in patients with diffuse large B-cell lymphoma. Blood Adv. 2021;5:4762–70.
Google Scholar
Blum KA, Supko JG, Maris MB, Flinn IW, Goy A, Younes A, et al. A phase I study of pelabresib (CPI-0610), a small-molecule inhibitor of BET proteins, in patients with relapsed or refractory lymphoma. Cancer Res Commun. 2022;2:795–805.
Google Scholar
Syahputra EW, Lee H, Cho H, Park HJ, Park K-S, Hwang D. PROTAC delivery strategies for overcoming physicochemical properties and physiological barriers in targeted protein degradation. Pharmaceutics. 2025;17:501.
Google Scholar
Li L, Mi D, Pei H, Duan Q, Wang X, Zhou W, et al. In vivo target protein degradation induced by PROTACs based on E3 ligase DCAF15. Signal Transduct Target Ther. 2020;5:129.
Google Scholar
Hanzl A, Casement R, Imrichova H, Hughes SJ, Barone E, Testa A, et al. Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders. Nat Chem Biol. 2023;19:323–33.
Google Scholar
Ottis P, Palladino C, Thienger P, Britschgi A, Heichinger C, Berrera M, et al. Cellular resistance mechanisms to targeted protein degradation converge toward impairment of the engaged ubiquitin transfer pathway. ACS Chem Biol. 2019;14:2215–23.
Zhang L, Riley-Gillis B, Vijay P, Shen Y. Acquired resistance to BET-PROTACs (proteolysis-targeting chimeras) caused by genomic alterations in core components of E3 ligase complexes. Mol Cancer Ther. 2019;18:1302–11.
Google Scholar
Dale B, Cheng M, Park K-S, Kaniskan HÜ, Xiong Y, Jin J. Advancing targeted protein degradation for cancer therapy. Nat Rev Cancer. 2021;21:638–54.
Google Scholar
Li Z, Wan J, Li S, Tang Y, Lin YC, Ni J, et al. Multi-omics characterization of E3 regulatory patterns in different cancer types. Int J Mol Sci. 2024;25:7639.
Google Scholar
Tsai JM, Nowak RP, Ebert BL, Fischer ES. Targeted protein degradation: from mechanisms to clinic. Nat Rev Mol Cell Biol. 2024;25:740–57.
Google Scholar
Marei H, Tsai W-TK, Kee Y-S, Ruiz K, He J, Cox C, et al. Antibody targeting of E3 ubiquitin ligases for receptor degradation. Nature. 2022;610:182–9.
Google Scholar
Lim YS, Jeong N-R, Yoo S-M, Kim HW, Lee SH, Kim D-W. A novel BCR-ABL1 degrader, Ubx-362, can overcome resistance by BCR-ABL1 kinase domain mutations in chronic myeloid leukemia. Blood. 2023;142:5012.
Google Scholar
Moreno V, Vieito M, Sepulveda JM, Galvao V, Hernández-Guerrero T, Doger B, et al. BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas. Nat Commun. 2023;14:1359.
Google Scholar
Wang JS-Z, De Vita S, Karlix JL, Cook C, Littlewood GM, Hattersley MM, et al. First-in-human study of AZD5153, a small molecule inhibitor of bromodomain protein 4 (BRD4), in patients (pts) with relapsed/refractory (RR) malignant solid tumor and lymphoma: Preliminary data. J Clin Oncol. 2019;37:3085.
Google Scholar
