Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression.
The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50value of 51 pM in inhibition of RS4;11 cell growth and induces rapid tumor regression in vivo against RS4;11 xenograft tumors. These data establish that compound 23 (BETd-260/ZBC260) is a highly potent and efficacious BET degrader.
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Bing
0000-0003-1813-8035
B
Zhou
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Jiantao
J
Hu
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Fuming
F
Xu
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Zhuo
Z
Chen
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Longchuan
L
Bai
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Ester
E
Fernandez-Salas
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Mei
M
Lin
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Liu
L
Liu
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Chao-Yie
CY
Yang
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Yujun
Y
Zhao
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Donna
D
McEachern
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Sally
S
Przybranowski
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Bo
B
Wen
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Duxin
D
Sun
University of Michigan Comprehensive Cancer Center, and Departments of ‡Internal Medicine, §Pathology, ∥Pharmaceutical Sciences, ⊥Medicinal Chemistry, and #Pharmacology, University of Michigan , Ann Arbor, Michigan 48109, United States.
Shaomeng
0000-0002-8782-6950
S
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D059748:Proteolysis; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D007211:Indoles; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D016601:RNA-Binding Proteins; D054852:Small Molecule Libraries; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human