In-flow photooxygenation of aminothienopyridinones generates iminopyridinedione PTP4A3 phosphatase inhibitors

Tasker, Nikhil R.; Rastelli, Ettore J.; Blanco, Isabella K.; Burnett, James C.; Sharlow, Elizabeth R.; Lazo, John S.; Wipf, Peter

doi:10.1039/c9ob00025a

Cited by 13 publications

(17 citation statements)

References 60 publications

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“…Inhibition of PTP4A3 by JMS-053 and New Analogs. We recently synthesized a series of 19 analogs of the novel iminothienopyridinedione JMS-053, which is a reversible, allosteric, and cell-active small molecule PTP4A3 inhibitor with an in vitro IC 50 value of ∼30 nM for recombinant human PTP4A3 (Salamoun et al, 2016;McQueeney et al, 2017McQueeney et al, , 2018Tasker et al, 2019). From the series, three JMS-053 analogs, EJR-866-75, EJR-866-81, and NRT-870-59 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…From the series, three JMS-053 analogs, EJR-866-75, EJR-866-81, and NRT-870-59 ( Fig. 1), were selected for further study because they retained the ability to potently inhibit PTP4A3 in vitro and had structural features that potentially should reduce metabolism or increase water solubility (Tasker et al, 2019). We also synthesized the valuable inactive congener JMS-053 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…7-Amino-2-phenyl-5H-thieno[3,2-c] pyridin-4-one (thienopyridone), 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5-8-dione (DA-3003-1), JMS-053, the inactive control compound 6-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (JMS-038), 7-imino-2-(4-(2-morpholinoethoxy)phenyl)thieno[3,2-c]pyridine-4,6(5H,7H)-dione (EJR-866-75), 2-(2-chlorophenyl)-7-iminothieno[3,2c]pyridine-4,6(5H,7H)-dione (EJR-866-81), and 7-imino-5-methyl-2phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione (NRT-870-59) ( Fig. 1) were synthesized as previously described (Brisson et al, 2005;Salamoun et al, 2016;Tasker et al, 2019). 6,8-Difluoro-4-methyl-umbelliferyl phosphate (DiFMUP) was purchased from ThermoFisher Scientific (Waltham, MA).…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, cancer cells are known to produce more ROS than nontransformed cells (Schieber and Chandel, 2014) and at least 12 clinically used anticancer drugs either directly or indirectly generate ROS (Yokoyama et al, 2017). Recent studies have shown that many proteins become oxidized at cysteine residues under conditions that increase intracellular ROS levels (van der Reest et al, 2018). Several classes of attractive therapeutic targets are susceptible to ROS-mediated inactivation, including metalloenzymes, cysteine proteases, and PTPs, because they contain a cysteine in their active site, which is readily deprotonated as a consequence of the surrounding peptide side chain functionality (Pani et al, 2000;Johnston et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, in the current report, we investigated the ability of JMS-053 and several recently synthesized analogs of JMS-053 to generate ROS and to inhibit PTP4A family members. We also biochemically tested our previously described computational models of the interactions between JMS-053 and PTP4A3 (McQueeney et al, 2017;Tasker et al, 2019) and interrogated the cytotoxicity of the JMS-053 analogs to human and mouse cancer cells to further clarify the actions of these compounds as chemical biology tools.…”

Section: Introductionmentioning

confidence: 99%

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Next-Generation Cell-Active Inhibitors of the Undrugged Oncogenic PTP4A3 Phosphatase

Lazo

Blanco

Tasker

et al. 2019

J Pharmacol Exp Ther

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Oncogenic protein tyrosine phosphatases (PTPs) are overexpressed in numerous human cancers but they have been challenging pharmacological targets. The emblematic oncogenic PTP4A tyrosine phosphatase family regulates many fundamental malignant processes. 7-Imino-2-phenylthieno[3,2c]pyridine-4,6(5H,7H)-dione (JMS-053) is a novel, potent, and selective PTP4A inhibitor but its mechanism of action has not been fully elucidated, nor has the chemotype been fully investigated. Because tyrosine phosphatases are notoriously susceptible to oxidation, we interrogated JMS-053 and three newly synthesized analogs with specific attention on the role of oxidation. JMS-053 and its three analogs were potent in vitro PTP4A3 inhibitors, but 7-imino-5-methyl-2-phenylthieno[3,2-c] pyridine-4,6(5H,7H)-dione (NRT-870-59) appeared unique among the thienopyridinediones with respect to its inhibitory specificity for PTP4A3 versus both a PTP4A3 A111S mutant and an oncogenic dual specificity tyrosine phosphatase, CDC25B. Like JMS-053, NRT-870-59 was a reversible PTP4A3 inhibitor. All of the thienopyridinediones retained cytotoxicity against human ovarian and breast cancer cells grown as pathologically relevant three-dimensional spheroids. Inhibition of cancer cell colony formation by NRT-870-59, like JMS-053, required PTP4A3 expression. JMS-053 failed to generate significant detectable reactive oxygen species in vitro or in cancer cells. Mass spectrometry results indicated no disulfide bond formation or oxidation of the catalytic Cys104 after in vitro incubation of PTP4A3 with JMS-053 or NRT-870-59. Gene expression profiling of cancer cells exposed to JMS-053 phenocopied many of the changes seen with the loss of PTP4A3 and did not indicate oxidative stress. These data demonstrate that PTP4A phosphatases can be selectively targeted with small molecules that lack prominent reactive oxygen species generation and encourage further studies of this chemotype. SIGNIFICANCE STATEMENT Protein tyrosine phosphatases are emerging as important contributors to human cancers. We report on a new class of reversible protein phosphatase small molecule inhibitors that are cytotoxic to human ovarian and breast cancer cells, do not generate significant reactive oxygen species in vitro and in cells, and could be valuable lead molecules for future studies of PTP4A phosphatases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Next-Generation Cell-Active Inhibitors of the Undrugged Oncogenic PTP4A3 Phosphatase

Lazo

Blanco

Tasker

et al. 2019

J Pharmacol Exp Ther

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A Palladium(0)‐Catalyzed C4 Site‐Selective C−H Difluoroalkylation of Isoquinolin‐1(2H)‐Ones

2021

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Herein, we report a Palladium(0)‐catalyzed C4 site‐selective C−H difluoroalkylation of isoquinolin‐1(2H)‐ones through a radical pathway. The present reaction enables the preparation of 2,2‐difluoro‐2‐(1‐oxo‐1,2‐dihydroisoquinolin‐4‐yl)acetates/acetamides through the direct cross‐coupling reaction of readily available isoquinolin‐1(2H)‐ones with 2‐bromo‐2,2‐difluoroacetates or 2‐bromo‐2,2‐difluoroacetamides. Therefore, this method provides an efficient and convenient approach to install a difluoroacetate or a difluoroacetamide moiety into bioactive molecules. Bioassay results showed that introduction of these difluorinated groups at C4 position was beneficial to improve their antiviral activity and compound 5 ab was found to exhibit similar antiviral activity with commercial Ningnanmycin.

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A Straightforward One‐Step Access to Ticlopidine Derivatives Arylated at the C5‐Position of the Thienyl Ring via Pd‐Catalyzed Direct Arylations

Atoui

Salem

et al. 2019

Asian J Org Chem

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The reactivity of Ticlopidine, which belongs to the thienopyridine drug family, in Pd-catalyzed CÀ H bond functionalization was investigated. The use of a palladiumdiphosphine catalyst associated to potassium acetate base in N,N-dimethylacetamide was found to promote the regioselective arylation at the C5-position of the Ticlopidine thienyl ring with aryl bromides in high yields. In the course of this reaction, no dechlorination or debenzylation of the 2chlorobenzyl group of Ticlopidine was observed. A wide Asian J = 7.8 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 4H), 7.42 (d, J = 7.7 Hz, 1H), 7.34-7.22 (m, 2H), 6.89 (s, 1H), 3.92 (s, 2H), 3.75 (s, 2H), 3.03-2.95 (m, 4H). 13 4 5 6 7 8

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In-flow photooxygenation of aminothienopyridinones generates iminopyridinedione PTP4A3 phosphatase inhibitors

Abstract: A continuous flow photooxygenation of 7-aminothieno[3,2-c]pyridin-4(5H)-ones produces potent in vitro inhibitors of the cancer-associated protein tyrosine phosphatase PTP4A3.

Cited by 13 publications

References 60 publications

Next-Generation Cell-Active Inhibitors of the Undrugged Oncogenic PTP4A3 Phosphatase

Next-Generation Cell-Active Inhibitors of the Undrugged Oncogenic PTP4A3 Phosphatase

A Palladium(0)‐Catalyzed C4 Site‐Selective C−H Difluoroalkylation of Isoquinolin‐1(2H)‐Ones

A Straightforward One‐Step Access to Ticlopidine Derivatives Arylated at the C5‐Position of the Thienyl Ring via Pd‐Catalyzed Direct Arylations

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