2-Anilino-4-(thiazol-5-yl)pyrimidine CDK Inhibitors:  Synthesis, SAR Analysis, X-ray Crystallography, and Biological Activity

Wang, Shudong; Meades, Christopher; Wood, Graham R.; Osnowski, Andrew P.; Anderson, Sian; Yuill, R.; Thomas, Mark; Mezna, Mokdad; Jackson, Wayne; Midgley, Carol A.; Griffiths, G.; Fleming, Ian N.; Green, Simon R.; McNae, I.W.; Wu, Su-Ying; McInnes, Campbell; Zheleva, Daniella; Walkinshaw, Malcolm D.; Fischer, Peter M.

doi:10.1021/jm0309957

Cited by 155 publications

(184 citation statements)

References 40 publications

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“…Standard MTT (thiazolyl blue; 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays were performed as reported previously (Wang et al, 2004). In brief, cells were seeded (1500-3000 cells/well) in 96-well plates and allowed to attach overnight.…”

Section: Methodsmentioning

confidence: 99%

In Vitro Antitumor Mechanism of (E)-N-(2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)pyridin-3-yl)methanesulfonamide

Laughton

Wang

et al. 2014

Mol Pharmacol

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ON01910.Na [sodium (E)-2-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl) methyl)phenylamino)acetate; Rigosertib, Estybon], a styryl benzylsulfone, is a phase III stage anticancer agent. This non-ATP competitive kinase inhibitor has multitargeted activity, promoting mitotic arrest and apoptosis. Extensive phase I/II studies with ON01910.Na, conducted in patients with solid tumors and hematologic cancers, demonstrate excellent efficacy. However, issues remain affecting its development. These include incomplete understanding of antitumor mechanisms, low oral bioavailability, and unpredictable pharmacokinetics. We have identified a novel (E)-styrylsulfonyl methylpyridine [(E)-N-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl) pyridin-3-yl)methanesulfonamide (TL-77)] which has shown improved oral bioavailability compared with ON01910.Na. Here, we present detailed cellular mechanisms of TL-77 in comparison with ON01910.Na. TL-77 displays potent growth inhibitory activity in vitro (GI 50 , 1mM against HCT-116 cells), demonstrating 3-to 10-fold greater potency against tumor cell lines when compared with normal cells. Cell-cycle analyses reveal that TL-77 causes significant G2/M arrest in cancer cells, followed by the onset of apoptosis. In cell-free conditions, TL-77 potently inhibits tubulin polymerization. Mitotically arrested cells display multipolar spindles and misalignment of chromosomes, indicating that TL-77 interferes with mitotic spindle assembly in cancer cells. These effects are accompanied by induction of DNA damage, inhibition of Cdc25C phosphorylation [indicative of Plk1 inhibition], and downstream inhibition of cyclin B1. However, kinase assays failed to confirm inhibition of Plk1. Nonsignificant effects on phosphoinositide 3-kinase/Akt signal transduction were observed after TL-77 treatment. Analysis of apoptotic signaling pathways reveals that TL-77 downregulates expression of B-cell lymphoma 2 family proteins (Bid, Bcl-xl, and Mcl-1) and stimulates caspase activation. Taken together, TL-77 represents a promising anticancer agent worthy of further evaluation.

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Section: Methodsmentioning

confidence: 99%

In Vitro Antitumor Mechanism of (E)-N-(2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)pyridin-3-yl)methanesulfonamide

Laughton

Wang

et al. 2014

Mol Pharmacol

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“…Protein X-ray Crystallography-Expression, purification, and crystallization of monomeric human CDK2, as well as ligand introduction, data collection, processing, structure solution, and refinement, were all carried out using methods analogous to those previously described for complex structures with non-cytokinin CDK2 ligands (28,29). Data collection and refinement statistics for the CDK2-ANCYT1 complex are presented in Table S2 (supplemental Table 2).…”

Section: Methodsmentioning

confidence: 99%

Classical Anticytokinins Do Not Interact with Cytokinin Receptors but Inhibit Cyclin-dependent Kinases

Spíchal

Kryštof

Paprskářová

et al. 2007

Journal of Biological Chemistry

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Cytokinins are a class of plant hormones that regulate the cell cycle and diverse developmental and physiological processes. Several compounds have been identified that antagonize the effects of cytokinins. Based on structural similarities and competitive inhibition, it has been assumed that these anticytokinins act through a common cellular target, namely the cytokinin receptor. Here, we examined directly the possibility that various representative classical anticytokinins inhibit the Arabidopsis cytokinin receptors CRE1/AHK4 (cytokinin response 1/Arabidopsis histidine kinase 4) and AHK3 (Arabidopsis histidine kinase 3). We show that pyrrolo Cytokinins are plant hormones that play essential roles in the regulation of various aspects of plant growth and development (1). They include a variety of chemicals with different degrees of structural similarity, some of which occur naturally in plants, and others that are known only as synthetic compounds. The natural cytokinins are adenine derivatives that can be classified according to the nature of their N 6 -side chain as either isoprenoid (zeatin) or aromatic (benzyladenine) cytokinins.Cytokinins are key regulators of the plant cell cycle, and the induction of cell division is considered diagnostic for this class of plant hormones. The molecular basis of this activity is only partially understood and may differ in different cell types. Cytokinins have been found to control tyrosine dephosphorylation and activation of p34 cdc2 -like H1 histone kinase (2), as well as the transcriptional activation of cyclin D3 (3). Some of the many physiological and developmental processes that are controlled by cytokinin, such as the formation and activity of shoot apical meristems, floral development, the breaking of bud dormancy, and seed germination (4 -8), are at least in part functionally linked to cell cycle control.Recently, several cytokinin receptors were identified in Arabidopsis (9 -12) and Zea mays (13). To date, three cytokinin receptors have been identified in Arabidopsis, AHK2, 4 AHK3, and CRE1/AHK4. All are membrane-located sensor histidine kinases with a predicted extracellular ligand-binding domain and cytoplasmic His kinase and receiver domains. It has been shown that the cytokinin signal is transmitted by a multistep phospho-relay system through a complex form of the two-component signaling pathway that has long been known in prokaryotes and lower eukaryotes. Among higher eukaryotes, the two-component signaling pathway is only found in plants (reviewed by Refs. 14 -17).

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“…We decided to pursue CDK inhibition because of the similarity of our compounds and those described in the literature taking urea moiety into account 21,49,50 . Moreover a link between inhibition of CDKs and antiproliferative effect has been well documented [51][52][53][54] . CDK2 is often deregulated in cancer cells usually by cyclin overexpression or loss of natural inhibitors and provides cells with growth advantage.…”

Section: Cdk Inhibitionmentioning

confidence: 98%

Discovery of nitroaryl urea derivatives with antiproliferative properties

Wróbel¹,

Kiełbus

Kaczor

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of urea derivatives bearing nitroaryl moiety has been synthesized and assayed for their potential antiproliferative activities. Some of the tested compounds displayed activity in RK33 laryngeal cancer cells and TE671 rhabdomyosarcoma cells while being generally less toxic to healthy HSF human fibroblasts cells. One compound was demonstrated to be a moderate CDK2 inhibitor with IC 50 ¼ 14.3 mM. Its structure was solved by an X-ray crystallography and molecular modelling was performed to determine structure-activity relationship. Obtained compounds constitute novel structures and generally demonstrated greater cytotoxicity in comparison to cisplatin. This study offers new structural motifs with potential for further development.

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2-Anilino-4-(thiazol-5-yl)pyrimidine CDK Inhibitors: Synthesis, SAR Analysis, X-ray Crystallography, and Biological Activity

Cited by 155 publications

References 40 publications

In Vitro Antitumor Mechanism of (E)-N-(2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)pyridin-3-yl)methanesulfonamide

In Vitro Antitumor Mechanism of (E)-N-(2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)pyridin-3-yl)methanesulfonamide

Classical Anticytokinins Do Not Interact with Cytokinin Receptors but Inhibit Cyclin-dependent Kinases

Discovery of nitroaryl urea derivatives with antiproliferative properties

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