BRD4 PROTAC degrader MZ1 exerts anticancer effects in acute myeloid leukemia by targeting c-Myc and ANP32B genes

References

• Creutzig U, Zimmermann M, Bourquin JP, Dworzak MN, Fleischhack G, Graf N, Klingebiel T, Kremens B, Lehrnbecher T, von Neuhoff C, et al. Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004. Blood. 2013;122(1):37–43. DOI:10.1182/blood-2013-02-484097.
   PubMed Web of Science ®Google Scholar
• Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–447. DOI:10.1182/blood-2016-08-733196.
   PubMed Web of Science ®Google Scholar
• Aplenc R, Meshinchi S, Sung L, Alonzo T, Choi J, Fisher B, Gerbing R, Hirsch B, Horton T, Kahwash S, et al. Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the children’s oncology group. Haematologica. 2020;105(7):1879–1886. DOI:10.3324/haematol.2019.220962.
   PubMed Web of Science ®Google Scholar
• Rasche M, Zimmermann M, Borschel L, Bourquin JP, Dworzak M, Klingebiel T, Lehrnbecher T, Creutzig U, Klusmann JH, Reinhardt D. Successes and challenges in the treatment of pediatric acute myeloid leukemia: a retrospective analysis of the AML-BFM trials from 1987 to 2012. Leukemia. 2018;32(10):2167–2177. DOI:10.1038/s41375-018-0071-7.
   PubMed Web of Science ®Google Scholar
• Lange BJ, Smith FO, Feusner J, Barnard DR, Dinndorf P, Feig S, Heerema NA, Arndt C, Arceci RJ, Seibel N, et al. Outcomes in CCG-2961, a children’s oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children’s oncology group. Blood. 2008;111(3):1044–1053. DOI:10.1182/blood-2007-04-084293.
   PubMed Web of Science ®Google Scholar
• Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728–1740. DOI:10.1056/NEJMoa1902688.
   PubMed Web of Science ®Google Scholar
• Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell. 2014;54(5):728–736. DOI:10.1016/j.molcel.2014.05.016.
   PubMed Web of Science ®Google Scholar
• Segura MF, Fontanals-Cirera B, Gaziel-Sovran A, Guijarro MV, Hanniford D, Zhang G, Gonzalez-Gomez P, Morante M, Jubierre L, Zhang W, et al. BRD4 sustains melanoma proliferation and represents a new target for epigenetic therapy. Cancer Res. 2013;73(20):6264–6276. DOI:10.1158/0008-5472.CAN-13-0122-T.
   PubMed Web of Science ®Google Scholar
• Goundiam O, Gestraud P, Popova T, De la Motte Rouge T, Fourchotte V, Gentien D, Hupe P, Becette V, Houdayer C, Roman-Roman S, et al. Histo-genomic stratification reveals the frequent amplification/overexpression of CCNE1 and BRD4 genes in non-BRCAness high grade ovarian carcinoma. Int J Cancer. 2015;137(8):1890–1900. DOI:10.1002/ijc.29568.
   PubMed Web of Science ®Google Scholar
• Ferri E, Petosa C, McKenna CE, McKenna CE. Bromodomains:Structure,function and pharmacology of inhibition. Biochem Pharmacol. 2016;106:1–18. DOI:10.1016/j.bcp.2015.12.005.
   PubMed Web of Science ®Google Scholar
• Chen C, Xu L, Gao R, Wang S, Zhang Y, Wang C, Zeng C, Li Y. Transcriptome-based co-expression of BRD4 and PD-1/PD-L1 predicts poor overall survival in patients with acute myeloid leukemia. Front Pharmacol. 2021;11. DOI:10.3389/fphar.2020.582955.
   Web of Science ®Google Scholar
• Jiang G, Deng W, Liu Y, Wang C. General mechanism of JQ1 in inhibiting various types of cancer. Mol Med Rep. 2020;21(3):1021–1034. DOI:10.3892/mmr.2020.10927.
   PubMed Web of Science ®Google Scholar
• Lu Q, Ding X, Huang T, Zhang S, Li Y, Feng Z, Wang L, Zou X, Wang Y, Feng Z. BRD4 degrader ARV-825 produces long-lasting loss of BRD4 protein and exhibits potent efficacy against cholangiocarcinoma cells. Am J Transl Res. 2019;11(9):5728–5739.
   PubMed Web of Science ®Google Scholar
• Lim SL, Damnernsawad A, Shyamsunder P, Chng WJ, Han BC, Xu L, Pan J, Pravin DP, Alkan S, Tyner JW, et al. Proteolysis targeting chimeric molecules as therapy for multiple myeloma: efficacy, biomarker and drug combinations. Haematologica. 2019;104(6):1209–1220. DOI:10.3324/haematol.2018.201483.
   PubMed Web of Science ®Google Scholar
• Li X, Song Y. Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy. J Hematol Oncol. 2020;13(1):50. DOI:10.1186/s13045-020-00885-3.
   PubMed Web of Science ®Google Scholar
• Potjewyd F, Turner AW, Beri J, Rectenwald JM, Norris-Drouin JL, Cholensky SH, Margolis DM, Pearce KH, Herring LE, James LI. Degradation of polycomb repressive complex 2 with an EED-targeted bivalent chemical degrader. Cell Chem Biol. 2020;27(1):47–56 e15. DOI:10.1016/j.chembiol.2019.11.006.
   PubMed Web of Science ®Google Scholar
• S-M Q, Dong J, Z-Y X, Cheng X-D, Zhang W-D, Qin -J-J. PROTAC: an effective targeted protein degradation strategy for cancer therapy. Front Pharmacol. 2021;12:692574. DOI:10.3389/fphar.2021.692574.
   PubMed Web of Science ®Google Scholar
• Testa A, Lucas X, Castro GV, Chan K-H, Wright JE, Runcie AC, Gadd MS, Harrison WTA, E-J K, Fletcher D, et al. 3-Fluoro-4-hydroxyprolines: synthesis, conformational analysis, and stereoselective recognition by the VHL E3 ubiquitin ligase for targeted protein degradation. J Am Chem Soc. 2018;140(29):9299–9313. DOI:10.1021/jacs.8b05807.
   PubMed Web of Science ®Google Scholar
• Otto C, Schmidt S, Kastner C, Denk S, Kettler J, Müller N, Germer CT, Wolf E, Gallant P, Wiegering A. Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells. Neoplasia. 2019;21(11):1110–1120. DOI:10.1016/j.neo.2019.10.003.
   PubMed Web of Science ®Google Scholar
• Noblejas-López M, Nieto-Jimenez C, Burgos M, Gómez-Juárez M, Montero JC, Esparís-Ogando A, Pandiella A, Galán-Moya EM, Ocaña A. Activity of BET-proteolysis targeting chimeric (PROTAC) compounds in triple negative breast cancer. J Exp Clin Cancer Res. 2019;38(1):383. DOI:10.1186/s13046-019-1387-5.
   PubMed Web of Science ®Google Scholar
• Chan K-H, Zengerle M, Testa A, Ciulli A. Impact of target warhead and linkage vector on inducing protein degradation: comparison of Bromodomain and Extra-Terminal (BET) degraders derived from Triazolodiazepine (JQ1) and tetrahydroquinoline (I-BET726) BET inhibitor scaffolds. J Med Chem. 2017;61(2):504–513. DOI:10.1021/acs.jmedchem.6b01912.
   PubMed Web of Science ®Google Scholar
• Li Z, Yang C, Li X, Du X, Tao Y, Ren J, Fang F, Xie Y, Li M, Qian G, et al. The dual role of BI 2536, a small-molecule inhibitor that targets PLK1, in induction of apoptosis and attenuation of autophagy in neuroblastoma cells. J Cancer. 2020;11(11):3274–3287. DOI:10.7150/jca.33110.
   PubMed Web of Science ®Google Scholar
• Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9(4):357–359. DOI:10.1038/nmeth.1923.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nusbaum C, Myers RM, Brown M, Li W, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9(9):R137. DOI:10.1186/gb-2008-9-9-r137.
   PubMed Web of Science ®Google Scholar
• Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, Mesirov JP. Integrative genomics viewer. Nat Biotechnol. 2011;29(1):24–26. DOI:10.1038/nbt.1754.
   PubMed Web of Science ®Google Scholar
• Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153(2):307–319. DOI:10.1016/j.cell.2013.03.035.
   PubMed Web of Science ®Google Scholar
• Loven J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, Bradner JE, Lee TI, Young RA. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013;153(2):320–334. DOI:10.1016/j.cell.2013.03.036.
   PubMed Web of Science ®Google Scholar
• Devaiah BN, Singer DS. Two faces of brd4: mitotic bookmark and transcriptional lynchpin. Transcription. 2013;4(1):13–17. DOI:10.4161/trans.22542.
   PubMedGoogle Scholar
• BC V, A G, C A. Actual biological diagnosis of acute myeloblastic leukemia in children. J Med Life. 2014;7(2):291–295.
   PubMedGoogle Scholar
• Newell LF, Cook RJ. Advances in acute myeloid leukemia. BMJ. 2021;375:n2026. DOI:10.1136/bmj.n2026.
   PubMedGoogle Scholar
• Borck PC, Guo LW, Plutzky J. BET epigenetic reader proteins in cardiovascular transcriptional programs. Circ Res. 2020;126(9):1190–1208. DOI:10.1161/CIRCRESAHA.120.315929.
   PubMed Web of Science ®Google Scholar
• Hu Y, Zhou J, Ye F, Xiong H, Peng L, Zheng Z, Xu F, Cui M, Wei C, Wang X, et al. BRD4 inhibitor inhibits colorectal cancer growth and metastasis. Int J Mol Sci. 2015;16(1):1928–1948. DOI:10.3390/ijms16011928.
   PubMed Web of Science ®Google Scholar
• G-Q L, Guo W-Z, Zhang Y, X-X M, Zhang G, Li J, Yan B, Wang D, Zhang S-J, Tang H-W. Suppression of BRD4 inhibits human hepatocellular carcinoma by repressing MYC and enhancing BIM expression. Oncotarget. 2016;7(3):2462–2474. DOI:10.18632/oncotarget.6275.
   PubMedGoogle Scholar
• Zhang S, Zhao Y, Heaster TM, Fischer MA, Stengel KR, Zhou X, Ramsey H, Zhou -M-M, Savona MR, Skala MC, et al. BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML. J Cell Biochem. 2018. DOI:10.1002/jcb.28005.
   Web of Science ®Google Scholar
• Sang X, Zhang Y, Fang F, Gao L, Tao Y, Li X, Zhang Z, Wang J, Tian Y, Li Z, et al. BRD4 inhibitor GNE-987 exerts anticancer effects by targeting super-enhancer-related gene LYL1 in acute myeloid leukemia. J Immunology Res. 2022;2022:1–18. DOI:10.1155/2022/7912484.
   Google Scholar
• Doroshow DB, Eder JP, LoRusso PM. BET inhibitors: a novel epigenetic approach. Ann Oncol. 2017;28(8):1776–1787. DOI:10.1093/annonc/mdx157.
   PubMed Web of Science ®Google Scholar
• Dong X, Hu X, Chen J, Hu D, Chen LF. BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis. Cell Death Dis. 2018;9(2):203. DOI:10.1038/s41419-017-0181-6.
   PubMed Web of Science ®Google Scholar
• Zhou S, Zhang S, Wang L, Huang S, Yuan Y, Yang J, Wang H, Li X, Wang P, Zhou L, et al. BET protein inhibitor JQ1 downregulates chromatin accessibility and suppresses metastasis of gastric cancer via inactivating RUNX2/NID1 signaling. Oncogenesis. 2020;9(3):33. DOI:10.1038/s41389-020-0218-z.
   PubMed Web of Science ®Google Scholar
• Yang CY, Qin C, Bai L, Wang S. Small-molecule PROTAC degraders of the Bromodomain and Extra Terminal (BET) proteins - A review. Drug Discov Today Technol. 2019;31:43–51. DOI:10.1016/j.ddtec.2019.04.001.
   PubMedGoogle Scholar
• Dang CV. MYC on the path to cancer. Cell. 2012;149(1):22–35. DOI:10.1016/j.cell.2012.03.003.
   PubMed Web of Science ®Google Scholar
• Eilers M, Eisenman RN. Myc’s broad reach. Genes Dev. 2008;22(20):2755–2766. DOI:10.1101/gad.1712408.
   PubMed Web of Science ®Google Scholar
• Pang Y, Bai G, Zhao J, Wei X, Li R, Li J, Hu S, Peng L, Liu P, Mao H. The BRD4 inhibitor JQ1 suppresses tumor growth by reducing c-Myc expression in endometrial cancer. J Transl Med. 2022;20(1). DOI:10.1186/s12967-022-03545-x.
   PubMed Web of Science ®Google Scholar
• Goswami S, Mani R, Nunes J, Chiang C-L, Zapolnik K, Hu E, Frissora F, Mo X, Walker LA, Yan P, et al. PP2A is a therapeutically targetable driver of cell fate decisions via a c-Myc/p21 axis in human and murine acute myeloid leukemia. Blood. 2022;139(9):1340–1358. DOI:10.1182/blood.2020010344.
   PubMed Web of Science ®Google Scholar
• Hsieh Y-H, Ohno Y, Koizumi M, Nakayama H, Watanabe T, Hirooka M, Tokumoto Y, Kuroda T, Abe M, Fukuda S, et al. Downregulation of ANP32B exerts anti-apoptotic effects in hepatocellular carcinoma. Plos One. 2017;12(5). DOI:10.1371/journal.pone.0177343.
   Web of Science ®Google Scholar
• Yang S, Zhou L, Reilly PT, Shen SM, He P, Zhu XN, Li CX, Wang LS, Mak TW, Chen GQ, et al. ANP32B deficiency impairs proliferation and suppresses tumor progression by regulating AKT phosphorylation. Cell Death Dis. 2016;7(2):e2082. DOI:10.1038/cddis.2016.8.
   PubMedGoogle Scholar
• Reilly PT, Yu Y, Hamiche A, Wang L. Cracking the ANP32 whips: important functions, unequal requirement, and hints at disease implications. Bioessays. 2014;36(11):1062–1071. DOI:10.1002/bies.201400058.
   PubMed Web of Science ®Google Scholar