Discovery of ARD-2051 as a Potent and Orally Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer

被引：23

作者：

Han, Xin ^{[1
,2
]}

Zhao, Lijie ^{[1
,2
]}

Xiang, Weiguo ^{[1
,2
]}

Miao, Bukeyan ^{[1
,2
]}

Qin, Chong ^{[1
,2
]}

Wang, Mi ^{[1
,2
]}

Xu, Tianfeng ^{[1
,2
]}

McEachern, Donna ^{[1
,2
]}

Lu, Jianfeng ^{[1
,2
]}

Wang, Yu ^{[1
,2
]}

Metwally, Hoda ^{[1
,2
]}

Yang, Chao-Yie ^{[1
,2
]}

Kirchhoff, Paul D. D. ^{[1
,2
]}

Wang, Lu ^{[5
]}

Matvekas, Aleksas ^{[5
]}

Takyi-Williams, John ^{[5
]}

Wen, Bo ^{[5
]}

Sun, Duxin ^{[5
]}

Ator, Mark ^{[6
]}

Mckean, Robert ^{[6
]}

Wang, Shaomeng ^{[1
,2
,3
,4
]}

机构：

[1] Univ Michigan, Rogel Canc Ctr, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA

[6] Oncopia Therapeut Inc, Malvern, PA 19355 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 13期

关键词：

PROTEIN-DEGRADATION; UBIQUITINATION; MOLECULES;

D O I：

10.1021/acs.jmedchem.3c00405

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the discovery of ARD-2051as a potent and orally efficaciousandrogen receptor (AR) proteolysis-targeting chimera degrader. ARD-2051achieves DC50 values of 0.6 nM and D (max) >90% in inducing AR protein degradation in both theLNCaPand VCaP prostate cancer cell lines, potently and effectively suppressesAR-regulated genes, and inhibits cancer cell growth. ARD-2051 achievesa good oral bioavailability and pharmacokinetic profile in mouse,rat, and dog. A single oral dose of ARD-2051 strongly reduces AR proteinand suppresses AR-regulated gene expression in the VCaP xenografttumor tissue in mice. Oral administration of ARD-2051 effectivelyinhibits VCaP tumor growth and causes no signs of toxicity in mice.ARD-2051 is a promising AR degrader for advanced preclinical developmentfor the treatment of AR+ human cancers.

引用

页码：8822 / 8843

页数：22

共 50 条

[41] Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer
Tria, George S.
Abrams, Tinya
Baird, Jason
Burks, Heather E.
Firestone, Brant
Gaither, L. Alex
Hamann, Lawrence G.
He, Guo
Kirby, Christina A.
Kim, Sunkyu
Lombardo, Franco
Macchi, Kaitlin J.
McDonnell, Donald P.
Mishina, Yuji
Norris, John D.
Nunez, Jill
Springer, Clayton
Sun, Yingchuan
Thomsen, Noel M.
Wang, Chunrong
Wang, Jianling
Yu, Bing
Tiong-Yip, Choi-Lai
Peukert, Stefan
JOURNAL OF MEDICINAL CHEMISTRY, 2018, 61 (07) : 2837 - 2864
[42] Discovery of BMS-641988, a Novel and Potent Inhibitor of Androgen Receptor Signaling for the Treatment of Prostate Cancer
Attar, Ricardo M.
Jure-Kunkel, Maria
Balog, Aaron
Cvijic, Mary Ellen
Dell-John, Janet
Rizzo, Cheryl A.
Schweizer, Liang
Spires, Thomas E.
Platero, J. Suso
Obermeier, Mary
Shan, Weifang
Salvati, Mark E.
Foster, William R.
Dinchuk, Joseph
Chen, Shen-Jue
Vite, Gregory
Kramer, Robert
Gottardis, Marco M.
CANCER RESEARCH, 2009, 69 (16) : 6522 - 6530
[43] Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance
Salami, Jemilat
Alabi, Shanique
Willard, Ryan R.
Vitale, Nick J.
Wang, Jing
Dong, Hanqing
Jin, Meizhong
McDonnell, Donald P.
Crew, Andrew P.
Neklesa, Taavi K.
Crews, Craig M.
COMMUNICATIONS BIOLOGY, 2018, 1
[44] Updated results from VERITAC evaluating vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, in ER- positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer
Hurvitz, Sara
Schott, Anne
Ma, Cynthia
Nanda, Rita
Zahrah, George
Hunter, Natasha
Tan, Antoinette
Telli, Melinda
Mesias, Jesus Anampa
Jeselsohn, Rinath
Munster, Pamela
Zhi, Eric
Duperret, Elizabeth
Mather, Cecile
Hamilton, Erika
Han, Hyo
CANCER RESEARCH, 2024, 84 (09)
[45] Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance
Jemilat Salami
Shanique Alabi
Ryan R. Willard
Nick J. Vitale
Jing Wang
Hanqing Dong
Meizhong Jin
Donald P. McDonnell
Andrew P. Crew
Taavi K. Neklesa
Craig M. Crews
Communications Biology, 1
[46] DRUG-DRUG INTERACTION (DDI) STUDY OF THE PROTEOLYSIS TARGETING CHIMERA (PROTAC) ANDROGEN RECEPTOR (AR) DEGRADER BAVDEGALUTAMIDE IN COMBINATION WITH THE P-GLYCOPROTEIN (P-GP) SUBSTRATE FEXOFENADINE IN HEALTHY MALE VOLUNTEERS
Alicea, J.
Patel, V.
Ghent, B.
Dai, V.
Yu, T.
Jiang, J.
CLINICAL PHARMACOLOGY & THERAPEUTICS, 2024, 115 : S84 - S85
[47] VERITAC-2: a phase 3 study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ERpositive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer
Campone, Mario
Ma, Cynthia
de Laurentiis, Michelino
Iwata, Hiroji
Hurvitz, Sara
Wander, Seth
Danso, Michael
Lu, Dongrui
Smith, Julia Perkins
Liu, Yuan
Tran, Lana
Anderson, Sibyl
Hamilton, Erika
CANCER RESEARCH, 2024, 84 (09)
[48] Breaking androgen receptor addiction of prostate cancer by targeting different functional domains in the treatment of advanced disease
Maylin, Zoe R.
Nicolescu, Radu C. B.
Pandha, Hardev
Asim, Mohammad
TRANSLATIONAL ONCOLOGY, 2021, 14 (08):
[49] Vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, in ER plus /human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: Update of dose escalation results from a phase I/II trial
Hamilton, E. P.
Han, H.
Schott, A.
Tan, A.
Nanda, R.
Juric, D.
Hunter, N.
Munster, P.
Fang, B.
Zahrah, G.
Ranciato, J.
Gedrich, R.
Zhi, E.
Zhang, Y.
Tan, W.
Mather, C.
Perkins, J.
Anderson, S.
Hurvitz, S. A.
ANNALS OF ONCOLOGY, 2023, 34 : S344 - S344
[50] Targeting the N-Terminal Domain of the Androgen Receptor: A New Approach for the Treatment of Advanced Prostate Cancer
Antonarakis, Emmanuel S.
Chandhasin, Chandtip
Osbourne, Erica
Luo, Jun
Sadar, Marianne D.
Perabo, Frank
ONCOLOGIST, 2016, 21 (12): : 1427 - 1435

← 1 2 3 4 5 →