Discovery of a Positron Emission Tomography Radiotracer Selectively Targeting the BD1 Bromodomains of BET Proteins

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Feb 19

PMID 33603976

Citations 4

Authors

Ping Bai

Xiaoxia Lu

Yan Liu

Yu Lan

Hao Wang

Stephanie Fiedler

Robin Striar

Changning Wang

Affiliations

Soon will be listed here.

Abstract

In this paper, we report the design, synthesis, and biological evaluation of the first selective bromodomain and extra-terminal domain (BET) BD1 bromodomains of the PET radiotracer [F]PB006. The standard compound PB006 showed high affinity and good selectivity toward BRD4 BD1 ( = 100 nM and 29-fold selectively for BD1 over BD2) in an binding assay. PET imaging experiments in rodents were performed to evaluate the bioactivity of [F]PB006 . A biodistribution study of [F]PB006 in mice revealed high radiotracer uptake in peripheral tissues, such as liver and kidney, and moderate radiotracer uptake in the brain. Further blocking studies demonstrated the significant radioactivity decreasing (20-30% reduction compared with baseline) by pretreating unlabeled PB006 and JQ1, suggesting the high binding selectivity and specificity of [F]PB006. Our study indicated that [F]PB006 is a potent PET probe selectively targeting BET BD1, and further structural optimization of the radiotracer is still required to improve brain uptake to support neuroepigenetic imaging.

Citing Articles

The Development and Evaluation of a Novel Highly Selective PET Radiotracer for Targeting BET BD1.

Wang Y, Wang Y, Xu Y, Kang L, Tocci D, Wang C Pharmaceuticals (Basel). 2024; 17(10).

PMID: 39458928 PMC: 11509907. DOI: 10.3390/ph17101289.

Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease.

Bai P, Mondal P, Bagdasarian F, Rani N, Liu Y, Gomm A Acta Pharm Sin B. 2022; 12(10):3891-3904.

PMID: 36213537 PMC: 9532562. DOI: 10.1016/j.apsb.2022.05.017.

A positron emission tomography imaging probe selectively targeting the BD1 bromodomain and extra-terminal domain.

Bai P, Yan L, Bagdasarian F, Wilks M, Wey H, Wang C Chem Commun (Camb). 2022; 58(69):9654-9657.

PMID: 35943085 PMC: 9618257. DOI: 10.1039/d2cc03785h.

Visualization of Receptor-Interacting Protein Kinase 1 (RIPK1) by Brain Imaging with Positron Emission Tomography.

Lan Y, Bai P, Liu Y, Afshar S, Striar R, Rattray A J Med Chem. 2021; 64(20):15420-15428.

PMID: 34652135 PMC: 8858444. DOI: 10.1021/acs.jmedchem.1c01477.

References

Gosmini R, Nguyen V, Toum J, Simon C, Brusq J, Krysa G . The discovery of I-BET726 (GSK1324726A), a potent tetrahydroquinoline ApoA1 up-regulator and selective BET bromodomain inhibitor. J Med Chem. 2014; 57(19):8111-31. DOI: 10.1021/jm5010539. View

Hugle M, Lucas X, Weitzel G, Ostrovskyi D, Breit B, Gerhardt S . 4-Acyl Pyrrole Derivatives Yield Novel Vectors for Designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4(1). J Med Chem. 2016; 59(4):1518-30. DOI: 10.1021/acs.jmedchem.5b01267. View

Samanta S, Rajasingh S, Cao T, Dawn B, Rajasingh J . Epigenetic dysfunctional diseases and therapy for infection and inflammation. Biochim Biophys Acta Mol Basis Dis. 2016; 1863(2):518-528. PMC: 5222695. DOI: 10.1016/j.bbadis.2016.11.030. View

Baud M, Lin-Shiao E, Cardote T, Tallant C, Pschibul A, Chan K . Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes. Science. 2014; 346(6209):638-641. PMC: 4458378. DOI: 10.1126/science.1249830. View

Gallenkamp D, Gelato K, Haendler B, Weinmann H . Bromodomains and their pharmacological inhibitors. ChemMedChem. 2014; 9(3):438-64. DOI: 10.1002/cmdc.201300434. View

Gilan O, Rioja I, Knezevic K, Bell M, Yeung M, Harker N . Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. Science. 2020; 368(6489):387-394. PMC: 7610820. DOI: 10.1126/science.aaz8455. View

Chan K, 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. PMC: 5788402. DOI: 10.1021/acs.jmedchem.6b01912. View

Mirguet O, Gosmini R, Toum J, Clement C, Barnathan M, Brusq J . Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J Med Chem. 2013; 56(19):7501-15. DOI: 10.1021/jm401088k. View

Magistri M, Velmeshev D, Makhmutova M, Patel P, Sartor G, Volmar C . The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer's Disease. Curr Alzheimer Res. 2016; 13(9):985-95. PMC: 5026248. DOI: 10.2174/1567205013666160427101832. View

10.

Zhao Y, Zhou B, Bai L, Liu L, Yang C, Meagher J . Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor. J Med Chem. 2018; 61(14):6110-6120. PMC: 6489120. DOI: 10.1021/acs.jmedchem.8b00483. View

11.

Faivre E, McDaniel K, Albert D, Mantena S, Plotnik J, Wilcox D . Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer. Nature. 2020; 578(7794):306-310. DOI: 10.1038/s41586-020-1930-8. View

12.

Pike V . PET radiotracers: crossing the blood-brain barrier and surviving metabolism. Trends Pharmacol Sci. 2009; 30(8):431-40. PMC: 2805092. DOI: 10.1016/j.tips.2009.05.005. View

13.

Zhang G, Smith S, Zhou M . Discovery of Chemical Inhibitors of Human Bromodomains. Chem Rev. 2015; 115(21):11625-68. DOI: 10.1021/acs.chemrev.5b00205. View

14.

Garnier J, Sharp P, Burns C . BET bromodomain inhibitors: a patent review. Expert Opin Ther Pat. 2013; 24(2):185-99. DOI: 10.1517/13543776.2014.859244. View

15.

Doroshow D, Eder J, LoRusso P . BET inhibitors: a novel epigenetic approach. Ann Oncol. 2017; 28(8):1776-1787. DOI: 10.1093/annonc/mdx157. View

16.

Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith W, Fedorov O . Selective inhibition of BET bromodomains. Nature. 2010; 468(7327):1067-73. PMC: 3010259. DOI: 10.1038/nature09504. View

17.

Figge D, Standaert D . Dysregulation of BET proteins in levodopa-induced dyskinesia. Neurobiol Dis. 2017; 102:125-132. PMC: 5410664. DOI: 10.1016/j.nbd.2017.03.003. View

18.

Gacias M, Gerona-Navarro G, Plotnikov A, Zhang G, Zeng L, Kaur J . Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression. Chem Biol. 2014; 21(7):841-854. PMC: 4104156. DOI: 10.1016/j.chembiol.2014.05.009. View

19.

Skvortsova K, Iovino N, Bogdanovic O . Functions and mechanisms of epigenetic inheritance in animals. Nat Rev Mol Cell Biol. 2018; 19(12):774-790. DOI: 10.1038/s41580-018-0074-2. View

20.

Cochran A, Conery A, Sims 3rd R . Bromodomains: a new target class for drug development. Nat Rev Drug Discov. 2019; 18(8):609-628. DOI: 10.1038/s41573-019-0030-7. View