A Cancer Research UK Phase I Trial to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Aurora B Inhibitor GSK1070916A in Patients With Advanced Solid Tumors

RATIONALE: Aurora B/C kinase inhibitor GSK1070916A (GSK1070916A) may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PURPOSE: This phase I trial is studying the side effects and best dose of GSK1070916A in treating patients with advanced solid tumors.

Start Date01 Mar 2010

Sponsor / Collaborator

Cancer Research UK

100 Clinical Results associated with NMI-900

100 Translational Medicine associated with NMI-900

100 Patents (Medical) associated with NMI-900

Literatures (Medical) associated with NMI-900

01 Mar 2025·International Journal of Biological Macromolecules

Identification of chemical inhibitors targeting long noncoding RNA through gene signature-based high throughput screening

Article

Author: Gui, Yu ; Wang, Yumei ; Li, Shengrong ; Lin, Kequan ; Yu, Xiankuo ; An, Jun ; Huang, Lijun ; Wei, Mingming ; Wang, Dong ; Liao, Yile ; Tan, Xue ; Wang, Huili ; Hu, Chao ; Luo, Yan

Scalable methods for functionally high-throughput screening of RNA-targeting small molecules are currently limited. Here, an RNA knockdown gene signature and high-throughput sequencing-based high-throughput screening (HTS²) were integrated to identify RNA-targeting compounds. We first generated a gene signature characterizing the knockdown of the long non-coding RNA LINC00973. Then, screening of 8199 compounds by HTS² assay identified that treatments of Hesperadin and GSK1070916 significantly mimic the expression pattern of the LINC00973 knockdown gene signature. Functionally, cell phenotype changes after treatments of these two compounds also mimic the losing function of LINC00973 in multiple types of cancer cells. Mechanistically, the inhibitory action of these two compounds on LINC00973 primarily operates via the AURKB-mediated MAPK signaling pathway, resulting in reduced expression of the transcription factor c-Jun. Consequently, this leads to the suppression of LINC00973 transcription. Moreover, these two compounds significantly inhibit xenograft tumor growth in vivo. Clinically, we further found that breast tumors with high expression of LINC00973 also show relatively high expression of AURKB or JUN, and vice versa. In summary, we established a novel high-throughput screening strategy to identify small molecules capable of targeting RNA, provided two promising compounds targeting LINC00973 and further shed light on the underlying transcriptional upregulation mechanism of LINC00973 within cancer cells.

01 Jan 2025·Neoplasia

Aurora kinase B is required for growth and expansion of medulloblastoma cells in the tissue context

Article

Author: Zhang, Hanqing ; Allalou, Amin ; Neuhauss, Stephan C F ; Neuhauss, Stephan C.F. ; Özalp, Özgün ; Santhana Kumar, Karthiga ; Grotzer, Michael A. ; Baumgartner, Martin ; Gries, Alexandre ; Kuttler, Fabien ; Grotzer, Michael A ; Akle, Veronica

The impact of the tissue context on tumor growth and drug response in medulloblastoma (MB) is poorly understood. To gain insights into the growth and dissemination behavior of the MB tumor cells under treatment, we combined three-dimensional cell culture screening with ex vivo organotypic cerebellum slice co-culture (OCSC), which allowed the assessment of tumor cell behavior in the tissue context. To identify druggable kinase pathways involved in invasion, we screened a panel of 274 kinase inhibitors and identified aurora kinase B (AURKB) as a potential anti-invasion drug target in MB. We validated tumor suppressive activities of the AURKB inhibitor (AURKBi) Barasertib (AZD1152-HQPA) and the structurally unrelated compound GSK-1070916 in cerebellum slice culture models for SHH, and Grp3 MB. Importantly, AURKBi are tumor suppressive in the tissue context, also in MB tumor cells that are in vitro resistant to the same treatment. We confirmed the requirement of AURKB for tumor growth and expansion in the tissue context through genetic suppression of AURKB by siRNA. We revealed that the combination of AURKBi with the SRC/BCR-ABL inhibitor Dasatinib acts synergistically to repress tumor growth and expansion in the highly invasive MB cell model ONS-76, but not in Grp3 MB cells. We demonstrate that tumor growth in the tissue context is suppressed by pharmacological inhibition of AURKB, comparable to the growth reduction observed after X-ray irradiation, which was used as the positive control. Finally, we show that exposure to µM concentrations of Barasertib does not cause developmental toxicity in fish larvae. In conclusion, we demonstrate that AURKB is essential for MB tumor growth and expansion in the tissue context and the inhibition of AURKB is equally efficient as irradiation in repressing tumor cell growth. In patients younger than three years, pharmacological targeting of AURKB may thus constitute a novel means to overcome radiotherapy limitations.

01 Dec 2024·Purinergic Signalling

Machine learning-aided search for ligands of P2Y6 and other P2Y receptors

Article

Author: Gao, Zhan-Guo ; Lewicki, Sarah A ; Puhl, Ana C ; Ekins, Sean ; Makarov, Vadim ; Jacobson, Kenneth A ; Pramanik, Asmita

AbstractThe P2Y6 receptor, activated by uridine diphosphate (UDP), is a target for antagonists in inflammatory, neurodegenerative, and metabolic disorders, yet few potent and selective antagonists are known to date. This prompted us to use machine learning as a novel approach to aid ligand discovery, with pharmacological evaluation at three P2YR subtypes: initially P2Y6 and subsequently P2Y1 and P2Y14. Relying on extensive published data for P2Y6R agonists, we generated and validated an array of classification machine learning model using the algorithms deep learning (DL), adaboost classifier (ada), Bernoulli NB (bnb), k-nearest neighbors (kNN) classifier, logistic regression (lreg), random forest classifier (rf), support vector classification (SVC), and XGBoost (XGB) classifier models, and the common consensus was applied to molecular selection of 21 diverse structures. Compounds were screened using human P2Y6R-induced functional calcium transients in transfected 1321N1 astrocytoma cells and fluorescent binding inhibition at closely related hP2Y14R expressed in CHO cells. The hit compound ABBV-744, an experimental anticancer drug with a 6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine scaffold, had multifaceted interactions with the P2YR family: hP2Y6R inhibition in a non-surmountable fashion, suggesting that noncompetitive antagonism, and hP2Y1R enhancement, but not hP2Y14R binding inhibition. Other machine learning-selected compounds were either weak (experimental anti-asthmatic drug AZD5423 with a phenyl-1H-indazole scaffold) or inactive in inhibiting the hP2Y6R. Experimental drugs TAK-593 and GSK1070916 (100 µM) inhibited P2Y14R fluorescent binding by 50% and 38%, respectively, and all other compounds by < 20%. Thus, machine learning has led the way toward revealing previously unknown modulators of several P2YR subtypes that have varied effects.

100 Deals associated with NMI-900

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 2	-	GSK Plc	-
Ovarian Cancer	Preclinical	US	-	-
Non-Small Cell Lung Cancer	Discovery	US	Nemucore Medical Innovations, Inc.	14 Jul 2019
Philadelphia chromosome positive chronic myelogenous leukemia	Discovery	US	Nemucore Medical Innovations, Inc.	17 Jun 2019
Acute Myeloid Leukemia	Discovery	US	Nemucore Medical Innovations, Inc.	03 Jun 2019
Breast Cancer	Discovery	US	Nemucore Medical Innovations, Inc.	31 May 2019
Solid tumor	Discovery	GB	Cancer Research UK	27 Nov 2015
Advanced Malignant Solid Neoplasm	Discovery	GB	Cancer Research UK	01 Mar 2010

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01118611 (ASCO2013)	Phase 1	Solid tumor \| HR-positive/HER2-low Solid Tumors	38	GSK1070916A	(ndpctlnzcp) = zzvnacbdsa yybjapxtfn (pjnmbmeizl )	-	20 May 2013

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