Bromodomain and extra-terminal (BET) inhibitors in treating myeloid neoplasms

References

• Lawrence M, Daujat S, Schneider R. Lateral thinking: how histone modifications regulate gene expression. Trends Genet. 2016;32(1):42–56.
   PubMed Web of Science ®Google Scholar
• Holliday R. The inheritance of epigenetic defects. Science. 1987;238(4824):163–170.
   PubMed Web of Science ®Google Scholar
• Berger SL, Kouzarides T, Shiekhattar R, et al. An operational definition of epigenetics. Genes Dev. 2009;23(7):781–783.
   PubMed Web of Science ®Google Scholar
• Berry K, Wang J, Lu QR. Epigenetic regulation of oligodendrocyte myelination in developmental disorders and neurodegenerative diseases. F1000Res. 2020;9:105.
   Google Scholar
• Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl):245–254.
   PubMed Web of Science ®Google Scholar
• Schischlik F, Kralovics R. Mutations in myeloproliferative neoplasms - their significance and clinical use. Expert Rev Hematol. 2017;10(11):961–973.
   PubMed Web of Science ®Google Scholar
• Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome landscapes. Science. 2013;339(6127):1546–1558.
   PubMed Web of Science ®Google Scholar
• Oakes CC, Martin-Subero JI. Insight into origins, mechanisms, and utility of DNA methylation in B-cell malignancies. Blood. 2018;132(10):999–1006.
   PubMed Web of Science ®Google Scholar
• Nadeu F, Diaz-Navarro A, Delgado J, et al. Genomic and epigenomic alterations in chronic lymphocytic leukemia. Annu Rev Pathol. 2020;15:149–177.
   PubMed Web of Science ®Google Scholar
• Shih AH, Abdel-Wahab O, Patel JP, et al. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer. 2012;12(9):599–612.
   PubMed Web of Science ®Google Scholar
• Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358(11):1148–1159.
   PubMed Web of Science ®Google Scholar
• Cancer Genome Atlas Research N, Ley TJ, Miller C, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013; 368(22):2059–2074.
   PubMed Web of Science ®Google Scholar
• Zhang J, Zhong Q. Histone deacetylase inhibitors and cell death. Cell Mol Life Sci. 2014;71(20):3885–3901.
   PubMed Web of Science ®Google Scholar
• Zucchetti B, Shimada AK, Katz A, et al. The role of histone deacetylase inhibitors in metastatic breast cancer. Breast. 2019;43:130–134.
   PubMed Web of Science ®Google Scholar
• Allfrey VG, Faulkner R, Mirsky AE. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc Natl Acad Sci USA. 1964; 51:786–794.
   PubMed Web of Science ®Google Scholar
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674.
   PubMed Web of Science ®Google Scholar
• Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science. 2017;357(6348):eaal2380.
   PubMed Web of Science ®Google Scholar
• Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1):12–27.
   PubMed Web of Science ®Google Scholar
• Allis CD, Berger SL, Cote J, et al. New nomenclature for chromatin-modifying enzymes. Cell. 2007;131(4):633–636.
   PubMed Web of Science ®Google Scholar
• Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693–705.
   PubMed Web of Science ®Google Scholar
• Pott S, Lieb JD. What are super-enhancers? Nat Genet. 2015;47(1):8–12.
   PubMed Web of Science ®Google Scholar
• Whyte WA, Orlando DA, Hnisz D, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153(2):307–319.
   PubMed Web of Science ®Google Scholar
• Hnisz D, Abraham BJ, Lee TI, et al. Super-enhancers in the control of cell identity and disease. Cell. 2013;155(4):934–947.
   PubMed Web of Science ®Google Scholar
• Loven J, Hoke HA, Lin CY, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013;153(2):320–334.
   PubMed Web of Science ®Google Scholar
• Kim TK, Gore SD, Zeidan AM. Epigenetic therapy in acute myeloid leukemia: current and future directions. Semin Hematol. 2015;52(3):172–183.
   PubMed Web of Science ®Google Scholar
• Ungerstedt JS. Epigenetic modifiers in myeloid malignancies: the role of histone deacetylase inhibitors. Int J Mol Sci. 2018;19(10). DOI:10.3390/ijms19103091
   PubMed Web of Science ®Google Scholar
• Qi J. Bromodomain and extraterminal domain inhibitors (BETi) for cancer therapy: chemical modulation of chromatin structure. Cold Spring Harb Perspect Biol. 2014;6(12):a018663.
   PubMed Web of Science ®Google Scholar
• Filippakopoulos P, Picaud S, Mangos M, et al. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell. 2012;149(1):214–231.
   PubMed Web of Science ®Google Scholar
• Filippakopoulos P, Knapp S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov. 2014;13(5):337–356.
   PubMed Web of Science ®Google Scholar
• Perez-Salvia M, Esteller M. Bromodomain inhibitors and cancer therapy: From structures to applications. Epigenetics. 2017;12(5):323–339.
   PubMed Web of Science ®Google Scholar
• Zeng L, Zhou MM. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 2002;513(1):124–128.
   PubMed Web of Science ®Google Scholar
• Yang Z, Yik JH, Chen R, et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell. 2005;19(4):535–545.
   PubMed Web of Science ®Google Scholar
• Jang MK, Mochizuki K, Zhou M, et al. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell. 2005;19(4):523–534.
   PubMed Web of Science ®Google Scholar
• Yang Z, He N, Zhou Q. Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. Mol Cell Biol. 2008;28(3):967–976.
   PubMed Web of Science ®Google Scholar
• Denis GV, Vaziri C, Guo N, et al. RING3 kinase transactivates promoters of cell cycle regulatory genes through E2F. Cell Growth Differ. 2000;11(8):417–424.
   PubMedGoogle Scholar
• Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904–917.
   PubMed Web of Science ®Google Scholar
• Zou Z, Huang B, Wu X, et al. Brd4 maintains constitutively active NF-κB in cancer cells by binding to acetylated RelA. Oncogene. 2014;33(18):2395–2404.
   PubMed Web of Science ®Google Scholar
• Dawson MA, Prinjha RK, Dittmann A, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011;478(7370):529–533.
   PubMed Web of Science ®Google Scholar
• Vidler LR, Brown N, Knapp S, et al. Druggability analysis and structural classification of bromodomain acetyl-lysine binding sites. J Med Chem. 2012;55(17):7346–7359.
   PubMed Web of Science ®Google Scholar
• Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of BET bromodomains. Nature. 2010;468(7327):1067–1073.
   PubMed Web of Science ®Google Scholar
• Liu Z, Wang P, Chen H, et al. Drug discovery targeting bromodomain-containing protein 4. J Med Chem. 2017;60(11):4533–4558.
   PubMed Web of Science ®Google Scholar
• Lockwood WW, Zejnullahu K, Bradner JE, et al. Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proc Natl Acad Sci USA. 2012;109(47):19408–19413.
   PubMed Web of Science ®Google Scholar
• Mazur PK, Herner A, Mello SS, et al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med. 2015;21(10):1163–1171.
   PubMed Web of Science ®Google Scholar
• McCleland ML, Mesh K, Lorenzana E, et al. CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016;126(2):639–652.
   PubMed Web of Science ®Google Scholar
• Liu F, Hon GC, Villa GR, et al. EGFR mutation promotes glioblastoma through epigenome and transcription factor network remodeling. Mol Cell. 2015;60(2):307–318.
   PubMed Web of Science ®Google Scholar
• Herait PE, Berthon C, Thieblemont C, et al. Abstract CT231: BET-bromodomain inhibitor OTX015 shows clinically meaningful activity at nontoxic doses: interim results of an ongoing phase I trial in hematologic malignancies. Cancer Research. 2014;74(19 Supplement):CT231–CT231.
   Web of Science ®Google Scholar
• Emadali A, Hoghoughi N, Duley S, et al. Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms. Blood. 2016;127(24):3040–3053.
   PubMed Web of Science ®Google Scholar
• Sashida G, Wang C, Tomioka T, et al. The loss of Ezh2 drives the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition. J Exp Med. 2016;213(8):1459–1477.
   PubMed Web of Science ®Google Scholar
• Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci USA. 2011;108(40):16669–16674.
   PubMed Web of Science ®Google Scholar
• Zuber J, Shi J, Wang E, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011;478(7370):524–528.
   PubMed Web of Science ®Google Scholar
• Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937–951.
   PubMed Web of Science ®Google Scholar
• Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–2405.
   PubMed Web of Science ®Google Scholar
• Pemmaraju N, Konopleva M, Lane AA. More on blastic plasmacytoid dendritic-cell neoplasms. N Engl J Med. 2019;380(7):695–696.
   PubMed Web of Science ®Google Scholar
• Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380(17):1628–1637.
   PubMed Web of Science ®Google Scholar
• Feuillard J, Jacob MC, Valensi F, et al. Clinical and biologic features of CD4(+)CD56(+) malignancies. Blood. 2002;99(5):1556–1563.
   PubMed Web of Science ®Google Scholar
• Economides MP, Rizzieri D, Pemmaraju N. Updates in novel therapies for blastic plasmacytoid dendritic cell neoplasm (BPDCN). Curr Hematol Malig Rep. 2019;14(6):515–522.
   PubMed Web of Science ®Google Scholar
• Ceribelli M, Hou ZE, Kelly PN, et al. A Druggable TCF4- and BRD4-dependent transcriptional network sustains malignancy in blastic plasmacytoid dendritic cell neoplasm. Cancer Cell. 2016;30(5):764–778.
   PubMed Web of Science ®Google Scholar
• Sukswai N, Aung PP, Yin CC, et al. Dual expression of TCF4 and CD123 is highly sensitive and specific for blastic plasmacytoid dendritic cell neoplasm. Am J Surg Pathol. 2019;43(10):1429–1437.
   PubMed Web of Science ®Google Scholar
• Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054–1061.
   PubMed Web of Science ®Google Scholar
• Economides MP, Verstovsek S, Pemmaraju N. Novel therapies in myeloproliferative neoplasms (MPN): beyond JAK inhibitors. Curr Hematol Malig Rep. 2019;14(5):460–468.
   PubMed Web of Science ®Google Scholar
• Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–798.
   PubMed Web of Science ®Google Scholar
• Quintas-Cardama A, Kantarjian H, Cortes J, et al. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov. 2011;10(2):127–140.
   PubMed Web of Science ®Google Scholar
• Kleppe M, Koche R, Zou L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(4):785–787.
   PubMed Web of Science ®Google Scholar
• Boi M, Todaro M, Vurchio V, et al. Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes. Oncotarget. 2016;7(48):79637–79653.
   PubMedGoogle Scholar
• Riveiro ME, Astorgues-Xerri L, Vazquez R, et al. OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations. Oncotarget. 2016; 7(51):84675–84687.
   PubMedGoogle Scholar
• Astorgues-Xerri L, Riveiro ME, Tijeras-Raballand A, et al. OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis. Eur J Cancer. 2014;50(14):2463–2477.
   PubMed Web of Science ®Google Scholar
• Vazquez R, Riveiro ME, Astorgues-Xerri L, et al. The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus. Oncotarget. 2017;8(5):7598–7613.
   PubMedGoogle Scholar
• Coude MM, Braun T, Berrou J, et al. BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget. 2015;6(19):17698–17712.
   PubMedGoogle Scholar
• Odore E, Lokiec F, Cvitkovic E, et al. Phase I population pharmacokinetic assessment of the oral bromodomain inhibitor OTX015 in patients with haematologic malignancies. Clin Pharmacokinet. 2016;55(3):397–405.
   PubMed Web of Science ®Google Scholar
• Albrecht BK, Gehling VS, Hewitt MC, et al. Identification of a benzoisoxazoloazepine inhibitor (CPI-0610) of the bromodomain and extra-terminal (BET) family as a candidate for human clinical trials. J Med Chem. 2016;59(4):1330–1339.
   PubMed Web of Science ®Google Scholar
• Liu PC, Liu XM, Stubbs MC, et al. Abstract 3523: discovery of a novel BET inhibitor INCB054329. Cancer Research. 2015;75(15 Supplement):3523–3523.
   Google Scholar
• Stubbs MC, Burn TC, Sparks R, et al. The novel bromodomain and extraterminal domain inhibitor INCB054329 induces vulnerabilities in myeloma cells that inform rational combination strategies. Clin Cancer Res. 2019;25(1):300–311.
   PubMed Web of Science ®Google Scholar
• Stubbs MC, Maduskuie T, Burn T, et al. Abstract 5071: Preclinical characterization of the potent and selective BET inhibitor INCB057643 in models of hematologic malignancies. Cancer Research. 2017;77(13 Supplement):5071–5071.
   Google Scholar
• Pemmaraju N, Borate U, Solh M, et al. Dose escalation study of BET inhibitor PLX2853 in patients with relapsed or refractory acute myeloid leukemia or high risk myelodysplastic syndrome. Blood. 2019;134(Supplement_1):1391–1391.
   Web of Science ®Google Scholar
• Ozer HG, El-Gamal D, Powell B, et al. BRD4 profiling identifies critical chronic lymphocytic leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor. Cancer Discov. 2018;8(4):458–477.
   PubMed Web of Science ®Google Scholar
• McDaniel KF, Wang L, Soltwedel T, et al. Discovery of N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin -4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a potent and orally available bromodomain and extraterminal domain (BET) Family bromodomain inhibitor. J Med Chem. 2017;60(20):8369–8384.
   PubMed Web of Science ®Google Scholar
• Sarthy A, Li L, Albert DH, et al. Abstract 4718: ABBV-075, a novel BET family bromodomain inhibitor, represents a promising therapeutic agent for a broad spectrum of cancer indications. Cancer Research. 2016;76(14 Supplement):4718–4718.
   Google Scholar
• Bui MH, Lin X, Albert DH, et al. Preclinical characterization of BET family bromodomain inhibitor ABBV-075 suggests combination therapeutic strategies. Cancer Res. 2017;77(11):2976–2989.
   PubMed Web of Science ®Google Scholar
• Fiskus W, Cai T, DiNardo CD, et al. Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells. Blood Cancer J. 2019;159(2):4.
   PubMed Web of Science ®Google Scholar
• Berthon C, Raffoux E, Thomas X, et al. Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study. Lancet Haematol. 2016;3(4):e186-95–e195.
   PubMed Web of Science ®Google Scholar
• Falchook G, Rosen S, LoRusso P, et al. Development of 2 bromodomain and extraterminal inhibitors with distinct pharmacokinetic and pharmacodynamic profiles for the treatment of advanced malignancies. Clin Cancer Res. 2020;26(6):1247–1257.
   PubMed Web of Science ®Google Scholar
• Millan DS, Alvarez Morales MA, Barr KJ, et al. FT-1101: A structurally distinct Pan-BET bromodomain inhibitor with activity in preclinical models of hematologic malignancies. Blood. 2015;126(23):1367–1367.
   PubMed Web of Science ®Google Scholar
• Shapiro GI, Dowlati A, LoRusso PM, et al. Clinically efficacy of the BET bromodomain inhibitor TEN-010 in an open-label substudy with patients with documented NUT-midline carcinoma (NMC). Mol Cancer Ther. 2015;14(12, Supplement 2). Abstract no. A49-A49.
   Google Scholar
• Nicodeme E, Jeffrey KL, Schaefer U, et al. Suppression of inflammation by a synthetic histone mimic. Nature. 2010;468(7327):1119–1123.
   PubMed Web of Science ®Google Scholar
• John Mascarenhas M, Kremyanskaya M, Hoffman R, MD, et al. MD PhD. MANIFEST, a phase 2 study of CPI-0610, a bromodomain and extraterminal domain inhibitor (BETi), as monotherapy or "add-on" to ruxolitinib, in patients with refractory or intolerant advanced myelofibrosis blood. Blood. 2019;134:670–670.
   Google Scholar
• Fong CY, Gilan O, Lam EY, et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature. 2015;525(7570):538–542.
   PubMed Web of Science ®Google Scholar
• Rathert P, Roth M, Neumann T, et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature. 2015;525(7570):543–547.
   PubMed Web of Science ®Google Scholar
• Kurimchak AM, Shelton C, Duncan KE, et al. Resistance to BET bromodomain inhibitors is mediated by kinome reprogramming in ovarian cancer. Cell Rep. 2016;16(5):1273–1286.
   PubMed Web of Science ®Google Scholar
• Shu S, Lin CY, He HH, et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature. 2016;529(7586):413–417.
   PubMed Web of Science ®Google Scholar
• Pawar A, Gollavilli PN, Wang S, et al. Resistance to BET inhibitor leads to alternative therapeutic vulnerabilities in castration-resistant prostate cancer. Cell Rep. 2018;22(9):2236–2245.
   PubMed Web of Science ®Google Scholar
• Guo L, Li J, Zeng H, et al. A combination strategy targeting enhancer plasticity exerts synergistic lethality against BETi-resistant leukemia cells. Nat Commun. 2020;11(1):740.
   PubMed Web of Science ®Google Scholar
• Bhadury J, Nilsson LM, Muralidharan SV, et al. BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma. Proc Natl Acad Sci USA. 2014;111(26):E2721–30.
   PubMed Web of Science ®Google Scholar
• Fiskus W, Sharma S, Qi J, et al. Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 2014; 13(5):1142–1154.
   PubMed Web of Science ®Google Scholar
• Bui ML, Huang X, et al. The BET family bromodomain inhibitor ABBV-075 is a promising therapeutic agent for acute myeloid leukemia and myelodysplastic syndrome. Cancer Res. 2016;76 (14 Suppl). Abstrat no. 4738.
   Web of Science ®Google Scholar
• Liu XS, Ye M, et al. Combination of BET inhibitor INCB054329 and LSD1 inhibitor INCB059872 is synergistic for the treatment of AML in vitro and in vivo. Cancer Res. 2016;76:4702.
   Web of Science ®Google Scholar
• Yang CY, Qin C, Bai L, et al. Small-molecule PROTAC degraders of the Bromodomain and Extra Terminal (BET) proteins - a review. Drug Discov Today Technol. 2019;31:43–51.
   PubMedGoogle Scholar
• Sakamoto KM, Kim KB, Kumagai A, et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci USA. 2001;98(15):8554–8559.
   PubMed Web of Science ®Google Scholar
• Winter GE, Buckley DL, Paulk J, et al. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015;348(6241):1376–1381.
   PubMed Web of Science ®Google Scholar
• Saenz DT, Fiskus W, Qian Y, 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(9):1951–1961.
   PubMed Web of Science ®Google Scholar
• Mu X, Bai L, Xu Y, et al. Protein targeting chimeric molecules specific for dual bromodomain 4 (BRD4) and Polo-like kinase 1 (PLK1) proteins in acute myeloid leukemia cells. Biochem Biophys Res Commun. 2020;521(4):833–839.
   PubMed Web of Science ®Google Scholar
• Petrylak DP, Gao X, Vogelzang NJ, et al. First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI). J Clin Oncol. 2020;38(15_suppl):3500–3500.
   Google Scholar
• Amorim S, Stathis A, Gleeson M, et al. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol. 2016;3(4):e196–204.
   Google Scholar