Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Investigational New Drugs
Published in: Investigational New Drugs 3/2020

01-06-2020 | PRECLINICAL STUDIES

A new BET inhibitor, 171, inhibits tumor growth through cell proliferation inhibition more than apoptosis induction

Authors: Mohammadali Soleimani Damaneh, Jian-Ping Hu, Xia-Juan Huan, Shan-Shan Song, Chang-Qing Tian, Dan-Qi Chen, Tao Meng, Yue-Lei Chen, Jing-Kang Shen, Bing Xiong, Ze-Hong Miao, Ying-Qing Wang

Published in: Investigational New Drugs | Issue 3/2020

Login to get access

Summary

The bromodomain and extra-terminal domain (BET) family of proteins, especially bromodomain-containing protein 4 (BRD4), has emerged as exciting anti-tumor targets due to their important roles in epigenetic regulation. Therefore, the discovery of BET inhibitors with promising anti-tumor efficacy will provide a novel approach to epigenetic anticancer therapy. Recently, we discovered the new BET inhibitor compound 171, which is derived from a polo-like kinase 1 (PLK1)-BRD4 dual inhibitor based on our previous research. Compound 171 was found to maintain BET inhibition ability without PLK1 inhibition, and there was no selectivity among BET family members. The in vitro and in vivo results both indicated that the overall anti-tumor activity of compound 171 was improved compared with the (+)-JQ-1 or OTX-015 BET inhibitors. Furthermore, we found that compound 171 could regulate the expression of cell cycle-regulating proteins including c-Myc and p21 and induce cell cycle arrest in the G0/G1 phase. However, compound 171 only has a quite limited effect on apoptosis, in considering that apoptosis was only observed at doses greater than 50 μM. To determine the mechanisms underlying cell death, proliferation activity assay was conducted. The results showed that compound 171 induced clear anti-proliferative effects at doses that no obvious apoptosis was induced, which indicated that the cell cycle arresting effect contributed mostly to its anti-tumor activity. The result of this study revealed the anti-tumor mechanism of compound 171, and laid a foundation for the combination therapy in clinical practice, if compound 171 or its series compounds become drug candidates in the future.
Appendix
Available only for authorised users
Literature
1.
Taniguchi Y (2016) The bromodomain and extra-terminal domain (bet) family: functional anatomy of bet paralogous proteins. Int J Mol Sci 17:e1849PubMedCrossRef
2.
Li X, Baek G, Ramanand SG, Sharp A, Gao Y, Yuan W, Welti J, Rodrigues DN, Dolling D, Figueiredo I, Sumanasuriya S, Crespo M, Aslam A, Li R, Yin Y, Mukherjee B, Kanchwala M, Hughes AM, Halsey WS, Chiang CM, Xing C, Raj GV, Burma S, de Bono J, Mani RS (2018) Brd4 promotes DNA repair and mediates the formation of tmprss2-erg gene rearrangements in prostate cancer. Cell Rep 22:796–808PubMedPubMedCentralCrossRef
3.
Stanlie A, Yousif AS, Akiyama H, Honjo T, Begum NA (2014) Chromatin reader brd4 functions in ig class switching as a repair complex adaptor of nonhomologous end-joining. Mol Cell 55:97–110PubMedCrossRef
4.
5.
Jung M, Gelato KA, Fernandez-Montalvan A, Siegel S, Haendler B (2015) Targeting bet bromodomains for cancer treatment. Epigenomics 7:487–501PubMedCrossRef
6.
Fu LL, Tian M, Li X, Li JJ, Huang J, Ouyang L, Zhang YH, Liu B (2015) Inhibition of bet bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget 6:5501–5516PubMedPubMedCentralCrossRef
7.
Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thangue N, French CA, Wiest O, Kung AL, Knapp S, Bradner JE (2010) Selective inhibition of bet bromodomains. Nature 468:1067–1073PubMedPubMedCentralCrossRef
8.
Odore E, Lokiec F, Cvitkovic E, Bekradda M, Herait P, Bourdel F, Kahatt C, Raffoux E, Stathis A, Thieblemont C, Quesnel B, Cunningham D, Riveiro ME, Rezai K (2016) Phase i population pharmacokinetic assessment of the oral bromodomain inhibitor otx015 in patients with haematologic malignancies. Clin Pharmacokinet 55:397–405PubMedCrossRef
9.
Stathis A, Zucca E, Bekradda M, Gomez-Roca C, Delord JP, de La Motte Rouge T, Uro-Coste E, de Braud F, Pelosi G, French CA (2016) Clinical response of carcinomas harboring the brd4-nut oncoprotein to the targeted bromodomain inhibitor otx015/mk-8628. Cancer Discov 6:492–500PubMedPubMedCentralCrossRef
10.
Berthon C, Raffoux E, Thomas X, Vey N, Gomez-Roca C, Yee K, Taussig DC, Rezai K, Roumier C, Herait P, Kahatt C, Quesnel B, Michallet M, Recher C, Lokiec F, Preudhomme C, Dombret H (2016) Bromodomain inhibitor otx015 in patients with acute leukaemia: a dose-escalation, phase 1 study. Lancet Haematol 3:e186–e195PubMedCrossRef
11.
Amorim S, Stathis A, Gleeson M, Iyengar S, Magarotto V, Leleu X, Morschhauser F, Karlin L, Broussais F, Rezai K, Herait P, Kahatt C, Lokiec F, Salles G, Facon T, Palumbo A, Cunningham D, Zucca E, Thieblemont C (2016) Bromodomain inhibitor otx015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol 3:e196–e204PubMedCrossRef
12.
Yang ZY, He NH, Zhou Q (2008) Brd4 recruits p-ter to chromosomes at late mitosis to promote g(1) gene expression and cell cycle progression. Mol Cell Biol 28:967–976PubMedCrossRef
13.
Mochizuki K, Nishiyama A, Jang MK, Dey A, Ghosh A, Tamura T, Natsume H, Yao H, Ozato K (2008) The bromodomain protein brd4 stimulates g1 gene transcription and promotes progression to s phase. J Biol Chem 283:9040–9048PubMedPubMedCentralCrossRef
14.
Wang L, Wu X, Huang P, Lv Z, Qi Y, Wei X, Yang P, Zhang F (2016) Jq1, a small molecule inhibitor of brd4, suppresses cell growth and invasion in oral squamous cell carcinoma. Oncol Rep 36:1989–1996PubMedCrossRef
15.
Jostes S, Nettersheim D, Fellermeyer M, Schneider S, Hafezi F, Honecker F, Schumacher V, Geyer M, Kristiansen G, Schorle H (2017) The bromodomain inhibitor jq1 triggers growth arrest and apoptosis in testicular germ cell tumours in vitro and in vivo. J Cell Mol Med 21:1300–1314PubMedCrossRef
16.
Zhang S, Zhao Y, Heaster TM, Fischer MA, Stengel KR, Zhou X, Ramsey H, Zhou MM, Savona MR, Skala MC, Hiebert SW (2018) Bet inhibitors reduce cell size and induce reversible cell cycle arrest in aml. J Cell Biochem 120:7309–7322
17.
18.
Zhao LL, Cao DY, Chen TT, Wang YQ, Miao ZH, Xu YC, Chen WY, Wang X, Li YD, Du ZY, Xiong B, Li J, Xu CY, Zhang NX, He JH, Shen JK (2013) Fragment-based drug discovery of 2-thiazolidinones as inhibitors of the histone reader brd4 bromodomain. J Med Chem 56:3833–3851PubMedCrossRef
19.
Zhao LL, Wang YQ, Cao DY, Chen TT, Wang Q, Li YL, Xu YC, Zhang NX, Wang X, Chen DQ, Chen L, Chen YL, Xia GX, Shi Z, Liu YC, Lin YJ, Miao ZH, Shen JK, Xiong B (2015) Fragment-based drug discovery of 2-thiazolidinones as brd4 inhibitors: 2. Structure-based optimization. J Med Chem 58:1281–1297PubMedCrossRef
20.
Hu JP, Wang YQ, Li YL, Xu L, Cao DY, Song SS, Damaneh MS, Wang X, Meng T, Chen YL, Shen JK, Miao ZH, Xiong B (2017) Discovery of a series of dihydroquinoxalin-2(1h)-ones as selective bet inhibitors from a dual plk1-brd4 inhibitor. Eur J Med Chem 137:176–195PubMedCrossRef
21.
Hu JP, Wang YQ, Li YL, Cao DY, Xu L, Song SS, Damaneh MS, Li J, Chen YL, Wang X, Chen L, Shen JK, Miao ZH, Xiong B (2018) Structure-based optimization of a series of selective bet inhibitors containing aniline or indoline groups. Eur J Med Chem 150:156–175PubMedCrossRef
22.
Xu L, Wang W, Meng T, Ma LP, Tong LJ, Shen JK, Wang YQ, Miao ZH (2018) New microtubulin inhibitor mt189 suppresses angiogenesis via the jnk-vegf/vegfr2 signaling axis. Cancer Lett 416:57–65PubMedCrossRef
23.
Yi JM, Zhang XF, Huan XJ, Song SS, Wang W, Tian QT, Sun YM, Chen Y, Ding J, Wang YQ, Yang CH, Miao ZH (2015) Dual targeting of microtubule and topoisomerase ii by alpha-carboline derivative ych337 for tumor proliferation and growth inhibition. Oncotarget 6:8960–8973PubMedPubMedCentralCrossRef
24.
Wang W, Wang YQ, Meng T, Yi JM, Huan XJ, Ma LP, Tong LJ, Chen Y, Ding J, Shen JK, Miao ZH (2014) Mcl-1 degradation mediated by jnk activation via mekk1/tak1-mkk4 contributes to anticancer activity of new tubulin inhibitor mt189. Mol Cancer Ther 13:1480–1491PubMedCrossRef
25.
26.
Becker HM, Chen M, Hay JB, Cybulsky MI (2004) Tracking of leukocyte recruitment into tissues of mice by in situ labeling of blood cells with the fluorescent dye cfda se. J Immunol Methods 286:69–78PubMedCrossRef
27.
Schoffski P, Blay JY, De Greve J, Brain E, Machiels JP, Soria JC, Sleijfer S, Wolter P, Ray-Coquard I, Fontaine C, Munzert G, Fritsch H, Hanft G, Aerts C, Rapion J, Allgeier A, Bogaerts J, Lacombe D (2010) Multicentric parallel phase ii trial of the polo-like kinase 1 inhibitor bi 2536 in patients with advanced head and neck cancer, breast cancer, ovarian cancer, soft tissue sarcoma and melanoma. The first protocol of the european organization for research and treatment of cancer (eortc) network of core institutes (noci). Eur J Cancer 46:2206–2215PubMedCrossRef
28.
Mross K, Dittrich C, Aulitzky WE, Strumberg D, Schutte J, Schmid RM, Hollerbach S, Merger M, Munzert G, Fleischer F, Scheulen ME (2012) A randomised phase ii trial of the polo-like kinase inhibitor bi 2536 in chemo-naive patients with unresectable exocrine adenocarcinoma of the pancreas - a study within the central european society anticancer drug research (Cesar) collaborative network. Brit J Cancer 107:280–286PubMedCrossRefPubMedCentral
29.
Awad MM, Chu QS, Gandhi L, Stephenson JJ, Govindan R, Bradford DS, Bonomi PD, Ellison DM, Eaton KD, Fritsch H, Munzert G, Johnson BE, Socinski MA (2017) An open-label, phase ii study of the polo-like kinase-1 (plk-1) inhibitor, bi 2536, in patients with relapsed small cell lung cancer (sclc). Lung Cancer 104:126–130PubMedCrossRef
30.
Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, Bergeron L, Sims RJ 3rd (2011) Targeting myc dependence in cancer by inhibiting bet bromodomains. Proc Natl Acad Sci U S A 108:16669–16674PubMedPubMedCentralCrossRef
31.
Chaidos A, Caputo V, Gouvedenou K, Liu B, Marigo I, Chaudhry MS, Rotolo A, Tough DF, Smithers NN, Bassil AK, Chapman TD, Harker NR, Barbash O, Tummino P, Al-Mahdi N, Haynes AC, Cutler L, Le B, Rahemtulla A, Roberts I, Kleijnen M, Witherington JJ, Parr NJ, Prinjha RK, Karadimitris A (2014) Potent antimyeloma activity of the novel bromodomain inhibitors i-bet151 and i-bet762. Blood 123:697–705PubMedCrossRef
32.
Gallagher SJ, Mijatov B, Gunatilake D, Gowrishankar K, Tiffen J, James W, Jin L, Pupo G, Cullinane C, McArthur GA, Tummino PJ, Rizos H, Hersey P (2014) Control of nf-kb activity in human melanoma by bromodomain and extra-terminal protein inhibitor i-bet151. Pigment Cell Melanoma Res 27:1126–1137PubMedCrossRef
33.
34.
Shin SB, Woo SU, Yim H (2015) Differential cellular effects of plk1 inhibitors targeting the atp-binding domain or polo-box domain. J Cell Physiol 230:3057–3067PubMedCrossRef
35.
Dey A, Ellenberg J, Farina A, Coleman AE, Maruyama T, Sciortino S, Lippincott-Schwartz J, Ozato K (2000) A bromodomain protein, mcap, associates with mitotic chromosomes and affects g(2)-to-m transition. Mol Cell Biol 20:6537–6549PubMedPubMedCentralCrossRef
36.
Farina A, Hattori M, Qin J, Nakatani Y, Minato N, Ozato K (2004) Bromodomain protein brd4 binds to gtpase-activating spa-1, modulating its activity and subcellular localization. Mol Cell Biol 24:9059–9069PubMedPubMedCentralCrossRef
37.
Henssen A, Thor T, Odersky A, Heukamp L, El-Hindy N, Beckers A, Slpeleman F, Althoff K, Schafers S, Schramm A, Sure U, Fleischhack G, Eggert A, Schulte JH (2013) Bet bromodomain protein inhibition is a therapeutic option for medulloblastoma. Oncotarget 4:2080–2095PubMedPubMedCentralCrossRef
38.
Dawson MA, Gudgin EJ, Horton SJ, Giotopoulos G, Meduri E, Robson S, Cannizzaro E, Osaki H, Wiese M, Putwain S, Fong CY, Grove C, Craig J, Dittmann A, Lugo D, Jeffrey P, Drewes G, Lee K, Bullinger L, Prinjha RK, Kouzarides T, Vassiliou GS, Huntly BJ (2014) Recurrent mutations, including npm1c, activate a brd4-dependent core transcriptional program in acute myeloid leukemia. Leukemia 28:311–320PubMedCrossRef
39.
Lee DH, Qi J, Bradner JE, Said JW, Doan NB, Forscher C, Yang H, Koeffler HP (2015) Synergistic effect of jq1 and rapamycin for treatment of human osteosarcoma. Int J Cancer 136:2055–2064PubMedCrossRef
40.
Wong C, Laddha SV, Tang L, Vosburgh E, Levine AJ, Normant E, Sandy P, Harris CR, Chan CS, Xu EY (2014) The bromodomain and extra-terminal inhibitor cpi203 enhances the antiproliferative effects of rapamycin on human neuroendocrine tumors. Cell Death Dis 5:e1450PubMedPubMedCentralCrossRef
41.
Baker EK, Taylor S, Gupte A, Sharp PP, Walia M, Walsh NC, Zannettino ACW, Chalk AM, Burns CJ, Walkley CR (2015) Bet inhibitors induce apoptosis through a myc independent mechanism and synergise with cdk inhibitors to kill osteosarcoma cells. Sci Rep 5:10120PubMedPubMedCentralCrossRef
42.
Lam LT, Lin X, Faivre EJ, Yang Z, Huang X, Wilcox DM, Bellin RJ, Jin S, Tahir SK, Mitten M, Magoc T, Bhathena A, Kati WM, Albert DH, Shen Y, Uziel T (2017) Vulnerability of small-cell lung cancer to apoptosis induced by the combination of bet bromodomain proteins and bcl2 inhibitors. Mol Cancer Ther 16:1511–1520PubMedCrossRef
Metadata
Title
A new BET inhibitor, 171, inhibits tumor growth through cell proliferation inhibition more than apoptosis induction
Authors
Mohammadali Soleimani Damaneh
Jian-Ping Hu
Xia-Juan Huan
Shan-Shan Song
Chang-Qing Tian
Dan-Qi Chen
Tao Meng
Yue-Lei Chen
Jing-Kang Shen
Bing Xiong
Ze-Hong Miao
Ying-Qing Wang
Publication date
01-06-2020
Publisher
Springer US
Published in
Investigational New Drugs / Issue 3/2020
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-019-00818-z

Other articles of this Issue 3/2020

Investigational New Drugs 3/2020 Go to the issue

PRECLINICAL STUDIES

Stimulation of neuroendocrine differentiation in prostate cancer cells by GHRH and its blockade by GHRH antagonists

PHASE I STUDIES

Pharmacokinetic characteristics of vactosertib, a new activin receptor-like kinase 5 inhibitor, in patients with advanced solid tumors in a first-in-human phase 1 study

PRECLINICAL STUDIES

Dual functionality of the antimicrobial agent taurolidine which demonstrates effective anti-tumor properties in pediatric neuroblastoma

PRECLINICAL STUDIES

Tetra-substituted pyrrole derivatives act as potent activators of p53 in melanoma cells

PRECLINICAL STUDIES

LncRNA differentiation antagonizing non-protein coding RNA promotes proliferation and invasion through regulating miR-135a/NLRP37 axis in pancreatic cancer

PRECLINICAL STUDIES

Anticancer activity of a novel methylated analogue of L-mimosine against an in vitro model of human malignant melanoma
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits