Photooxygenation of an Amino-thienopyridone Yields a More Potent PTP4A3 Inhibitor

Overview

Journal Org Biomol Chem

Publisher Royal Society of Chemistry

Specialties Biochemistry
Chemistry

Date 2016 Jun 14

PMID 27291491

Citations 22

Authors

Joseph M Salamoun

Kelley E McQueeney

Kalyani Patil

Steven J Geib

Elizabeth R Sharlow

John S Lazo

Peter Wipf

Affiliations

Soon will be listed here.

Abstract

The phosphatase PTP4A3 is an attractive anticancer target, but knowledge of its exact role in cells remains incomplete. A potent, structurally novel inhibitor of the PTP4A family was obtained by photooxygenation of a less active, electron-rich thienopyridone (1). Iminothienopyridinedione 13 displays increased solution stability and is readily obtained by two new synthetic routes that converge in the preparation of 1. The late-stage photooxygenation of 1 to give 13 in high yield highlights the potential of this reaction to modify the structure and properties of a biological lead compound and generate value for expanding the scope of an SAR investigation. Analog 13 should become a valuable tool for further exploration of the role of PTP4A3 in tumor progression.

Citing Articles

Development of a high-throughput screening system targeting the protein-protein interactions between PRL and CNNM.

Funato Y, Mimura M, Nunomura K, Lin B, Fujii S, Haruta J Sci Rep. 2024; 14(1):25432.

PMID: 39455715 PMC: 11511866. DOI: 10.1038/s41598-024-76269-1.

Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells.

Chokshi C, Vaseem Shaikh M, Brakel B, Rossotti M, Tieu D, Maich W Nat Med. 2024; 30(10):2936-2946.

PMID: 39095594 DOI: 10.1038/s41591-024-03138-9.

In silico identification of putative druggable pockets in PRL3, a significant oncology target.

Bennett G, Starczewski J, Dela Cerna M Biochem Biophys Rep. 2024; 39:101767.

PMID: 39050014 PMC: 11267023. DOI: 10.1016/j.bbrep.2024.101767.

PRL3 as a therapeutic target for novel cancer immunotherapy in multiple cancer types.

Chia P, Ang K, Thura M, Zeng Q Theranostics. 2023; 13(6):1876-1891.

PMID: 37064866 PMC: 10091880. DOI: 10.7150/thno.79265.

Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders.

Stanford S, Bottini N Nat Rev Drug Discov. 2023; 22(4):273-294.

PMID: 36693907 PMC: 9872771. DOI: 10.1038/s41573-022-00618-w.

References

Mendgen T, Steuer C, Klein C . Privileged scaffolds or promiscuous binders: a comparative study on rhodanines and related heterocycles in medicinal chemistry. J Med Chem. 2011; 55(2):743-53. DOI: 10.1021/jm201243p. View

Wang H, Quah S, Dong J, Manser E, Tang J, Zeng Q . PRL-3 down-regulates PTEN expression and signals through PI3K to promote epithelial-mesenchymal transition. Cancer Res. 2007; 67(7):2922-6. DOI: 10.1158/0008-5472.CAN-06-3598. View

Gentile G, Bernasconi G, Pozzan A, Merlo G, Marzorati P, Bamborough P . Identification of 2-(4-pyridyl)thienopyridinones as GSK-3β inhibitors. Bioorg Med Chem Lett. 2011; 21(16):4823-7. DOI: 10.1016/j.bmcl.2011.06.050. View

Schreiber S, Kotz J, Li M, Aube J, Austin C, Reed J . Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes. Cell. 2015; 161(6):1252-65. PMC: 4564295. DOI: 10.1016/j.cell.2015.05.023. View

Roskoski Jr R . A historical overview of protein kinases and their targeted small molecule inhibitors. Pharmacol Res. 2015; 100:1-23. DOI: 10.1016/j.phrs.2015.07.010. View

Bialy L, Waldmann H . Inhibitors of protein tyrosine phosphatases: next-generation drugs?. Angew Chem Int Ed Engl. 2005; 44(25):3814-39. DOI: 10.1002/anie.200461517. View

Lazo J, Wipf P . Phosphatases as targets for cancer treatment. Curr Opin Investig Drugs. 2009; 10(12):1297-304. View

Min G, Lee S, Kim H, Han Y, Lee R, Jeong D . Rhodanine-based PRL-3 inhibitors blocked the migration and invasion of metastatic cancer cells. Bioorg Med Chem Lett. 2013; 23(13):3769-74. DOI: 10.1016/j.bmcl.2013.04.092. View

Guzinska-Ustymowicz K, Pryczynicz A . PRL-3, an emerging marker of carcinogenesis, is strongly associated with poor prognosis. Anticancer Agents Med Chem. 2011; 11(1):99-108. DOI: 10.2174/187152011794941145. View

10.

De Munter S, Kohn M, Bollen M . Challenges and opportunities in the development of protein phosphatase-directed therapeutics. ACS Chem Biol. 2012; 8(1):36-45. DOI: 10.1021/cb300597g. View

11.

George Rosenker K, Paquette W, Johnston P, Sharlow E, Vogt A, Bakan A . Synthesis and biological evaluation of 3-aminoisoquinolin-1(2H)-one based inhibitors of the dual-specificity phosphatase Cdc25B. Bioorg Med Chem. 2015; 23(12):2810-8. DOI: 10.1016/j.bmc.2015.01.043. View

12.

Simpson D, Katavic P, Lozama A, Harding W, Parrish D, Deschamps J . Synthetic studies of neoclerodane diterpenes from Salvia divinorum: preparation and opioid receptor activity of salvinicin analogues. J Med Chem. 2007; 50(15):3596-603. DOI: 10.1021/jm070393d. View

13.

Zimmerman M, Homanics G, Lazo J . Targeted deletion of the metastasis-associated phosphatase Ptp4a3 (PRL-3) suppresses murine colon cancer. PLoS One. 2013; 8(3):e58300. PMC: 3610886. DOI: 10.1371/journal.pone.0058300. View

14.

Liang F, Liang J, Wang W, Sun J, Udho E, Zhang Z . PRL3 promotes cell invasion and proliferation by down-regulation of Csk leading to Src activation. J Biol Chem. 2006; 282(8):5413-9. DOI: 10.1074/jbc.M608940200. View

15.

Zimmerman M, McQueeney K, Isenberg J, Pitt B, Wasserloos K, Homanics G . Protein-tyrosine phosphatase 4A3 (PTP4A3) promotes vascular endothelial growth factor signaling and enables endothelial cell motility. J Biol Chem. 2014; 289(9):5904-13. PMC: 3937659. DOI: 10.1074/jbc.M113.480038. View

16.

Fiordalisi J, Keller P, Cox A . PRL tyrosine phosphatases regulate rho family GTPases to promote invasion and motility. Cancer Res. 2006; 66(6):3153-61. DOI: 10.1158/0008-5472.CAN-05-3116. View

17.

Tang S, Lee Y, Packiaraj D, Ho H, Chai C . Systematic Evaluation of the Metabolism and Toxicity of Thiazolidinone and Imidazolidinone Heterocycles. Chem Res Toxicol. 2015; 28(10):2019-33. DOI: 10.1021/acs.chemrestox.5b00247. View

18.

Huryn D, Resnick L, Wipf P . Contributions of academic laboratories to the discovery and development of chemical biology tools. J Med Chem. 2013; 56(18):7161-76. PMC: 3785552. DOI: 10.1021/jm400132d. View

19.

Lazo J, Sharlow E . Drugging Undruggable Molecular Cancer Targets. Annu Rev Pharmacol Toxicol. 2015; 56:23-40. DOI: 10.1146/annurev-pharmtox-010715-103440. View

20.

Saha S, Bardelli A, Buckhaults P, Velculescu V, Rago C, St Croix B . A phosphatase associated with metastasis of colorectal cancer. Science. 2001; 294(5545):1343-6. DOI: 10.1126/science.1065817. View