Development of Highly Potent and Selective Diaminothiazole Inhibitors of Cyclin-Dependent Kinases

Schönbrunn, E.; Betzi, S.; Alam, R.; Martin, Mathew P.; Becker, Andreas; Han, Huijong; Francis, Rawle; Chakrasali, R. T.; Jakkaraj, Sudhakar; Kazi, Aslamuzzaman; Sebti, Saı̈d M.; Cubitt, Christopher L.; Gebhard, Anthony W.; Hazlehurst, Lori A.; Tash, Joseph S.; Georg, Gunda I.

doi:10.1021/jm301234k

Cited by 75 publications

(89 citation statements)

References 55 publications

(94 reference statements)

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“…In numerous types of cancer, excessive cell cycle proteins allow for fast growth of tumor cells (42,43). It has been demonstrated that abnormal CCND1 is present in breast, lung, endometrial, pancreatic and testicular cancer, multiple myeloma and other types of blood cancer (44)(45)(46)(47)(48). Mutation, amplification and over-expression of CCND1 may alter the cell cycle process.…”

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confidence: 99%

Role of microRNA-4458 in patients with non-small-cell lung cancer

et al. 2016

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Abstract. Incidence and progression of non-small-cell lung cancer (NSCLC) is a multi-factor, multi-step process. The present study investigated the association between the expression level of microRNA (miR)-4458 in NSCLC and paracarcinoma liver tissues and survival rates, and studied the biological functions of miR-4458 at the cellular and protein level. NSCLC and paracarcinoma tissues were sequenced using a miR expression chip. The association between miR-4458 expression and tumor-node-metastasis staging, total survival rate and relapse-free survival rate was analyzed. miR-4458 was subjected to target gene prediction. The target protein of cyclin D1 (CCND1) was verified with western blot analysis, immunohistochemistry and a luciferase reporter assay. The relative level of miR-4458 in paracarcinoma tissues of 9 NSCLC patients decreased from 2.38 to 0.65 (P<0.001). Total five-year survival rates of the high-expression miR-4458 group (29.21%) significantly exceeded that of the low-expression group (14.37%) (P=0.025). The viability of human lung carcinoma A549 and H460 cells transfected with miR-4458 decreased significantly compared with cells transfected with a normal control (blank control plasmid) within 72 h (P<0.001). The percentage of A549 and H460 cells transfected with a miR-4458 mimic at the cell cycle stage G0/G1 was 69.94±8.05 and 68.15±7.75%, respectively. The percentages increased significantly compared with the control group (46.06±6.93 for A549 cells; 45.22±7.24 for H640 cells; P<0.001). CCND1 mRNA was downregulated significantly in H460 cells 72 h subsequent to the addition of miR-4458 mimics (P<0.001). The activity of mutant-CCND1 altered slightly, while the fluorescence intensity of the wild-type-CCND1 group decreased significantly following the addition of miR-4458 mimics. In conclusion, miR-4458 was expressed at low levels in lung cancer tissues, and it arrested cells in vitro at stage G0/G1 and inhibited cell proliferation. Therefore, miR-4458 may participate in the onset of lung cancer as a suppressor gene by inhibiting CCND1.

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confidence: 99%

Role of microRNA-4458 in patients with non-small-cell lung cancer

et al. 2016

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“…[26] With an IC 50 value of 0.26 mm,i ti s moderately active against MST3 by establishing as ingle hydrogen bond with the hinge regiona nd multiple water-mediated hydrogen bonds with residues of the front-specificity pocket and the P-loop.D asatinib has been developeda sadual SRC/ ABL inhibitor, [27] exhibits anti-proliferationa nd apoptotic activity against aw ider ange of cancers, [28] and is an FDA-approved antineoplastic agent (trade name Sprycel). With an IC 50 value of 7.4 mm,d asatinib is aw eak inhibitor of MST3 likely duet o steric hindrance caused by the carboxamide linker protruding the chloromethylphenyl ring towardt he gatekeeper residue, which movesa way as ar esult.T he hydroxyphenyltriazine (TP) fragment was previously identified as aw eak CDK2 inhibitor in an HTS campaign (PDB ID:3 QQJ [29] )a nd served here to probe hinge binding potentialinM ST3.…”

Section: Sar Of Mst3 Inhibitorsmentioning

confidence: 99%

Discovery of Diverse Small‐Molecule Inhibitors of Mammalian Sterile20‐like Kinase 3 (MST3)

et al. 2016

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Increasing evidence suggests key roles for members of the mammalian Sterile20-like (MST) family of kinases in many aspects of biology. MST3 is a member of the STRIPAK complex, the deregulation of which has recently been associated with cancer cell migration and metastasis. Targeting MST3 with small-molecule inhibitors may be beneficial for the treatment of certain cancers, but little information exists on the potential of kinase inhibitor scaffolds to engage with MST3. In this study we screened MST3 against a library of 277 kinase inhibitors using differential scanning fluorimetry and confirmed 14 previously unknown MST3 inhibitors by X-ray crystallography. These compounds, of which eight are in clinical trials or FDA approved, comprise nine distinct chemical scaffolds that inhibit MST3 enzymatic activity with IC50 values between 0.003 and 23 μm. The structure-activity relationships explain the differential inhibitory activity of these compounds against MST3 and the structural basis for high binding potential, the information of which may serve as a framework for the rational design of MST3-selective inhibitors as potential therapeutics and to interrogate the function of this enzyme in diseased cells.

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“…Crystallographic structure of 9 was used as a starting conformation for molecular docking to a selected crystal structure of CDK2 (PDB ID: 3QXP) 20 . Molecular docking was performed using the induced-fit approach of Schrödinger software.…”

Section: Molecular Modellingmentioning

confidence: 99%

“…From many available X-ray structures of CDK2 in complex with inhibitors, 3QXP 20 was selected due to structural similarity of 9 to the complexed inhibitor. Figure 3 depicts the final binding pose of 9 (A) and this pose aligned to the reference ligand (B).…”

Section: Molecular Modellingmentioning

confidence: 99%

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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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Development of Highly Potent and Selective Diaminothiazole Inhibitors of Cyclin-Dependent Kinases

Cited by 75 publications

References 55 publications

Role of microRNA-4458 in patients with non-small-cell lung cancer

Role of microRNA-4458 in patients with non-small-cell lung cancer

Discovery of Diverse Small‐Molecule Inhibitors of Mammalian Sterile20‐like Kinase 3 (MST3)

Discovery of nitroaryl urea derivatives with antiproliferative properties

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