The Experts below are selected from a list of 11046 Experts worldwide ranked by ideXlab platform
Jonathan M Elkins - One of the best experts on this subject based on the ideXlab platform.
-
structural mechanism of synergistic activation of Aurora Kinase b c by phosphorylated incenp
Nature Communications, 2019Co-Authors: Kamal Abdul R Azeez, Sneha Chatterjee, Todd R Golub, Frank Sobott, Jonathan M ElkinsAbstract:Aurora Kinases B and C (AURKB/AURKC) are activated by binding to the C-terminal domain of INCENP. Full activation requires phosphorylation of two serine residues of INCENP that are conserved through evolution, although the mechanism of this activation has not been explained. Here we present crystal structures of the fully active complex of AURKC bound to INCENP, consisting of phosphorylated, activated, AURKC and INCENP phosphorylated on its TSS motif, revealing the structural and biochemical mechanism of synergistic activation of AURKC:INCENP. The structures show that TSS motif phosphorylation stabilises the Kinase activation loop of AURKC. The TSS motif phosphorylations alter the substrate-binding surface consistent with a mechanism of altered Kinase substrate selectivity and stabilisation of the protein complex against unfolding. We also analyse the binding of the most specific available AURKB inhibitor, BRD-7880, and demonstrate that the well-known Aurora Kinase inhibitor VX-680 disrupts binding of the phosphorylated INCENP TSS motif.
David Brunell - One of the best experts on this subject based on the ideXlab platform.
-
comprehensive pharmacogenomic profiling of human papillomavirus positive and negative squamous cell carcinoma identifies sensitivity to Aurora Kinase inhibition in kmt2d mutants
Cancer Letters, 2018Co-Authors: Nene N Kalu, Tuhina Mazumdar, Shaohua Peng, Pan Tong, Li Shen, Jing Wang, Upasana Banerjee, Jeffrey N Myers, Curtis R Pickering, David BrunellAbstract:To address the unmet need for effective biomarker-driven targeted therapy for human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) and cervical cancer, we conducted a high-throughput drug screen using 1122 compounds in 13 HPV-positive and 11 matched HPV-negative cell lines. The most effective drug classes were inhibitors of polo-like Kinase, proteasomes, histone deacetylase, and Aurora Kinases. Treatment with a pan-Aurora inhibitor, danusertib, led to G2M arrest and apoptosis in vitro. Furthermore, danusertib decreased tumor size compared with controls in patient derived xenograft models of HNSCC. To identify biomarkers predicting response, we determined associations between mutations and drug sensitivity. Our data and the Genomics of Drug Sensitivity in Cancer database showed that cancer cells with KMT2D mutations were more sensitive to Aurora Kinase inhibitors than were cells without mutations. Knockdown of KMT2D in wild-type cells led to increased Aurora Kinase inhibitor-induced apoptosis. We identified Aurora Kinase inhibitors as effective and understudied drugs in HNSCC and CESC. This is the first published study to demonstrate that mutations in KMT2D, which are common in many cancers, correlate with drug sensitivity in two independent datasets.
Hsing-pang Hsieh - One of the best experts on this subject based on the ideXlab platform.
-
CDKN1A-mediated responsiveness of MLL-AF4-positive acute lymphoblastic leukemia to Aurora Kinase-A inhibitors
International journal of cancer, 2014Co-Authors: Ya Ping Chen, Jang Yang Chang, Hsing-pang Hsieh, Hui Ju Lin, Jiann Shiuh Chen, Ming Ying Tsai, Nai Feng Chen, Kung Chao Chang, Wen Tsung HuangAbstract:Overexpression of Aurora Kinases is largely observed in many cancers, including hematologic malignancies. In this study, we investigated the effects and molecular mechanisms of Aurora Kinase inhibitors in acute lymphoblastic leukemia (ALL). Western blot analysis showed that both Aurora-A and Aurora-B are overexpressed in ALL cell lines and primary ALL cells. Both VE-465 and VX-680 effectively inhibited Aurora Kinase activities in nine ALL cell lines, which exhibited different susceptibilities to the inhibitors. Cells sensitive to Aurora Kinase inhibitors underwent apoptosis at an IC50 of ∼10-30 nM and displayed a phenotype of Aurora-A inhibition, whereas cells resistant to Aurora Kinase inhibitors (with an IC50 more than 10 μM) accumulated polyploidy, which may have resulted from Aurora-B inhibition. Drug susceptibility of ALL cell lines was not correlated with the expression level or activation status of Aurora Kinases. Interestingly, RS4;11 and MV4;11 cells, which contain the MLL-AF4 gene, were both sensitive to Aurora Kinase-A inhibitors treatment. Complementary DNA (cDNA) microarray analysis suggested that CDKN1A might govern the drug responsiveness of ALL cell lines in a TP53-independent manner. Most importantly, primary ALL cells with MLL-AF4 and CDKN1A expression were sensitive to Aurora Kinase inhibitors. Our study suggests CDKN1A could be a potential biomarker in determining the drug responsiveness of Aurora Kinase inhibitors in ALL, particularly in MLL-AF4-positive patients.
-
Advances in Aurora Kinase inhibitor patents
Expert opinion on therapeutic patents, 2009Co-Authors: Mohane Selvaraj Coumar, Chun Hei Antonio Cheung, Jang Yang Chang, Hsing-pang HsiehAbstract:Background: Aurora-A, Aurora-B and Aurora-C, members of serine/threonine Kinase family, play an important role in mitosis. They are essential for spindle assembly, centrosome maturation, chromosomal segregation and cytokinesis during mitosis. Abnormalities in the mitotic process as a result of overexpression/amplification of Aurora Kinase have been linked to genomic instability leading to tumorigenesis. Hence, the use of Aurora Kinase small-molecule inhibitors as a potential molecular-targeted therapeutic intervention for cancer is being pursued. Objective: A number of reviews focus on the biology of Aurora Kinase; a few focus on the medicinal chemistry aspect of Aurora Kinase inhibitor development. Here, we review the medicinal chemistry aspect of Aurora Kinase inhibitors, with a particular emphasis on the patent literature. Method: The Scifinder® and Delphion® databases were used to search the literature for Aurora Kinase inhibitors. Approximately 150 patents and 700 journal references are available, mo...
-
Structure-based design of novel pyrazoles as Aurora Kinase A inhibitors.
Nature Precedings, 2009Co-Authors: Mohane Coumar, Paritosh Shukla, Ajay Kumar Dixit, Jiun-shyang Leou, John Hsu, Hsing-pang HsiehAbstract:Inhibition of Aurora Kinase, a member of serine/threonine Kinase involved in the regulation of cell division is emerging as a new molecular targeted cancer treatment option. Three isoforms of Aurora Kinase, A, B and C are known. Both Aurora A and B are over expressed in many human cancers and are linked to chromosome instability, oncogenic transformation, tumour progression and development of chemoresistance. Inhibitors of Aurora Kinase, regardless of their Kinase specificity spectrum have shown to promote cancer cell death by induction of apoptosis and mitotic catastrophe. Based on the current success of Aurora Kinase inhibitors in the development of Kinase-based cancer therapy, we have initiated a structure-based virtual screening for the identification of Aurora Kinase inhibitors by using published Aurora protein structure (PDB code:1MQ4). Small molecule and natural product compound libraries were docked into the active site/ATP binding site using the programs Gold 3.0 and Glide 4.5. A total of six compounds were identified with high priority scores through this method to possess Aurora A inhibition. One of the virtual screen (VS) hit, BPR1K0025S0 was synthesised in 3 steps and found to have Aurora A IC50~15 M and x-ray co-crystal structure in complex with the Aurora protein was solved for this compound. Based on the binding mode of this compound to Aurora A protein, further modification in the ester part was envisaged and a total of around 40 compounds were synthesised. Many of them possessed enhanced activity level compared to the original hit. Of particular interest is the aniline series of compounds, which showed submicromolar activity in the enzyme based Aurora inhibition assay. Thus a forty-fold improvement in activity for BPR1K0269S0 was achieved from the initial virtual screen hit BPR1K0025S0.
-
Aurora Kinase inhibitors in preclinical and clinical testing
Expert opinion on investigational drugs, 2009Co-Authors: Chun Hei Antonio Cheung, Mohane Selvaraj Coumar, Hsing-pang Hsieh, Jang Yang ChangAbstract:Background: Mitosis is a key step in the cell cycle governing the distribution of genetic material to the daughter cells. Any aberration in this process could lead to genomic instability. Aurora A, B and C, are members of the serine/threonine Kinase family. Aurora Kinases are essential for spindle assembly, centrosome maturation, chromosomal segregation and cytokinesis during mitosis. Abnormalities in the mitotic process through overexpression/amplification of Aurora Kinase have been linked to genomic instability leading to tumorigenesis. Hence, use of Aurora Kinase small molecule inhibitors as potential molecular-targeted therapeutic intervention for cancer is being pursued by various researchers. Objective: To review the literature of Aurora Kinase inhibitors in clinical and preclinical testing. Method: Pubmed, Scifinder® and www.clinicaltrials.gov databases were used to search the literature for Aurora Kinase. Conclusion/results: Approximately 13 Aurora Kinase inhibitors are under Phase I/II evaluation...
Clara Nahmias - One of the best experts on this subject based on the ideXlab platform.
-
Reciprocal regulation of Aurora Kinase A and ATIP3 in the control of metaphase spindle length
Cellular and Molecular Life Sciences, 2020Co-Authors: Anne Nehlig, Claude Prigent, Cynthia Seiler, Yulia Steblyanko, Florent Dingli, Guillaume Arras, Damarys Loew, Julie Welburn, Marin Barisic, Clara NahmiasAbstract:Maintaining the integrity of the mitotic spindle in metaphase is essential to ensure normal cell division. We show here that depletion of microtubule-associated protein ATIP3 reduces metaphase spindle length. Mass spectrometry analyses identi-ied the microtubule minus-end depolymerizing kinesin Kif2A as an ATIP3 binding protein. We show that ATIP3 controls metaphase spindle length by interacting with Kif2A and its partner Dda3 in an Aurora Kinase A-dependent manner. In the absence of ATIP3, Kif2A and Dda3 accumulate at spindle poles, which is consistent with reduced poleward microtubule lux and shortening of the spindle. ATIP3 silencing also limits Aurora A localization to the poles. Transfection of GFP-Aurora A, but not Kinase-dead mutant, rescues the phenotype, indicating that ATIP3 maintains Aurora A activity on the poles to control Kif2A targeting and spindle size. Collectively, these data emphasize the pivotal role of Aurora Kinase A and its mutual regulation with ATIP3 in controlling spindle length.
Todd R Golub - One of the best experts on this subject based on the ideXlab platform.
-
structural mechanism of synergistic activation of Aurora Kinase b c by phosphorylated incenp
Nature Communications, 2019Co-Authors: Kamal Abdul R Azeez, Sneha Chatterjee, Todd R Golub, Frank Sobott, Jonathan M ElkinsAbstract:Aurora Kinases B and C (AURKB/AURKC) are activated by binding to the C-terminal domain of INCENP. Full activation requires phosphorylation of two serine residues of INCENP that are conserved through evolution, although the mechanism of this activation has not been explained. Here we present crystal structures of the fully active complex of AURKC bound to INCENP, consisting of phosphorylated, activated, AURKC and INCENP phosphorylated on its TSS motif, revealing the structural and biochemical mechanism of synergistic activation of AURKC:INCENP. The structures show that TSS motif phosphorylation stabilises the Kinase activation loop of AURKC. The TSS motif phosphorylations alter the substrate-binding surface consistent with a mechanism of altered Kinase substrate selectivity and stabilisation of the protein complex against unfolding. We also analyse the binding of the most specific available AURKB inhibitor, BRD-7880, and demonstrate that the well-known Aurora Kinase inhibitor VX-680 disrupts binding of the phosphorylated INCENP TSS motif.
