Synthesis and structure–activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors

Reichelt, Andreas; Bailis, Julie M.; Bartberger, Michael D.; Yao, Guomin; Hong, Shu; Kaller, Matthew R.; Allen, John G.; Weidner, Margaret F.; Keegan, Kathleen; Dao, Jennifer H.

doi:10.1016/j.ejmech.2014.04.013

Cited by 28 publications

(15 citation statements)

References 36 publications

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“…The serine/threonine kinase cell division cycle 7 (CDC7; also known as DBF4-dependent kinase) is an attractive target for novel drugs, which is activated by binding to its regulatory protein, DBF4; activated CDC7 kinase phosphorylates minichromosome maintenance 2 (MCM2) at Ser 40 to initiate DNA synthesis (11)(12)(13). Because of these central roles of CDC7 kinase in DNA replication (14)(15)(16)(17)(18)(19)(20), many CDC7 inhibitors are being developed as next-generation RS-inducing cancer drug candidates (11,12,21,22). We successfully developed the first orally active CDC7-selective inhibitor, TAK-931, which exhibited a broad spectrum of antitumor efficacy and showed unique mechanisms of action in various preclinical cancer models (22,23).…”

Section: Introductionmentioning

confidence: 99%

A CDC7 inhibitor sensitizes DNA-damaging chemotherapies by suppressing homologous recombination repair to delay DNA damage recovery

et al. 2021

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Cell division cycle 7 (CDC7), a serine/threonine kinase, plays important roles in DNA replication. We developed a highly specific CDC7 inhibitor, TAK-931, as a clinical cancer therapeutic agent. This study aimed to identify the potential combination partners of TAK-931 for guiding its clinical development strategies. Unbiased high-throughput chemical screening revealed that the highest synergistic antiproliferative effects observed were the combinations of DNA-damaging agents with TAK-931. Functional phosphoproteomic analysis demonstrated that TAK-931 suppressed homologous recombination repair activity, delayed recovery from double-strand breaks, and led to accumulation of DNA damages in the combination. Whole-genome small interfering RNA library screening identified sensitivity-modulating molecules, which propose the experimentally predicted target cancer types for the combination, including pancreatic, esophageal, ovarian, and breast cancers. The efficacy of combination therapy in these cancer types was preclinically confirmed in the corresponding primary-derived xenograft models. Thus, our findings would be helpful to guide the future clinical strategies for TAK-931.

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Section: Introductionmentioning

confidence: 99%

A CDC7 inhibitor sensitizes DNA-damaging chemotherapies by suppressing homologous recombination repair to delay DNA damage recovery

et al. 2021

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“…The apoptotic response induced in cancer cells by Cdc7 depletion is not mediated by p53 [ 13 ], but is activated by the stress-activated protein p38 MAPK in an ATR-dependent manner [ 14 ]. Thus, the fact that differential killing activity of Cdc7 inhibition has allowed for the development of small molecules targeting Cdc7 kinase for cancer therapy [ 4 , [15] , [16] , [17] , [18] , [19] , [20] , [21] ]. However, all Cdc7 inhibitors available so far target ATP binding region of the kinase, which will influence other kinase function due to sequence and structural similarity.…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Cdc7 Kinase Inhibitors as Anti-Cancer Agents that Target the Interaction with Dbf4 by the Fragment Complementation and Drug Repositioning Approach

Cheng

Yang

et al. 2018

EBioMedicine

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BackgroundCdc7-Dbf4 is a conserved serine/threonine kinase that plays an important role in initiation of DNA replication and DNA damage tolerance in eukaryotic cells. Cdc7 has been found overexpressed in human cancer cell lines and tumor tissues, and the knockdown of Cdc7 expression causes an p53-independent apoptosis, suggesting that Cdc7 is a target for cancer therapy. Only a handful Cdc7 kinase inhibitors have been reported. All Cdc7 kinase inhibitors, including PHA-767491, were identified and characterized as ATP-competitive inhibitors. Unfortunately, these ATP-competitive Cdc7 inhibitors have no good effect on clinical trial.MethodsHere, we have developed a novel drug-screening platform to interrupt the interaction between Cdc7 and Dbf4 based on Renilla reniformis luciferase (Rluc)-linked protein-fragment complementation assay (Rluc-PCA). Using drug repositioning approach, we found several promising Cdc7 inhibitors for cancer therapy from a FDA-approved drug library.FindingsOur data showed that dequalinium chloride and clofoctol we screened inhibit S phase progression, accumulation in G2/M phase, and Cdc7 kinase activity. In addition, in vivo mice animal study suggests that dequalinium chloride has a promising anti-tumor activity in oral cancer. Interestingly, we also found that dequalinium chloride and clofoctol sensitize the effect of platinum compounds and radiation due to synergistic effect. In conclusion, we identified non-ATP-competitive Cdc7 kinase inhibitors that not only blocks DNA synthesis at the beginning but also sensitizes cancer cells to DNA damage agents.InterpretationThe inhibitors will be a promising anti-cancer agent and enhance the therapeutic effect of chemotherapy and radiation for current cancer therapy.FundThis work was supported by grants from the Ministry of Science and Technology, Ministry of Health and Welfare, and National Health Research Institutes, Taiwan.

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“…However, since the synthesis of the 5-ester functionalised thiazoles like 2a, 2b is already described in the literature [8] we considered them as staring material. The reaction conditions for the Williamson ether formation was optimised by using NMP as a solvent, which led to better yields.…”

Section: Scheme 1: Retrosynthetic View Of Thiazole Synthesis Accordinmentioning

confidence: 99%

Decarboxylative Bromination of Thiazole Core and Consecutive Cross-Coupling Reactions

Freiberger¹,

Täuscher²,

Ritter³

et al. 2020

Preprint

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The 2,5-substituted 4-hydroxythiazoles form a fluorescent dye class with wide-range-tunable absorption and emission wavelengths. The insights gained on these heterocyclic fluorescence systems are intended to contribute to the development of alternative applications of such molecules in the various areas of biology, chemistry and technology. Therefore, a synthesis strategy for the bromination of the thiazole core was developed, which allows the implementation of various cross-coupling reactions on thiazoles. Furthermore, the so formed conjugated cross-coupling products are highly fluorescent and were investigated in terms of their spectroscopic properties.

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Synthesis and structure–activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors

Cited by 28 publications

References 36 publications

A CDC7 inhibitor sensitizes DNA-damaging chemotherapies by suppressing homologous recombination repair to delay DNA damage recovery

A CDC7 inhibitor sensitizes DNA-damaging chemotherapies by suppressing homologous recombination repair to delay DNA damage recovery

Identification of Novel Cdc7 Kinase Inhibitors as Anti-Cancer Agents that Target the Interaction with Dbf4 by the Fragment Complementation and Drug Repositioning Approach

Decarboxylative Bromination of Thiazole Core and Consecutive Cross-Coupling Reactions

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