- |||||||||| AT9283 / Otsuka, barasertib (AZD1152) / AstraZeneca, alisertib (MLN8237) / Puma
AURKA Kinase Controls Erythroblast Enucleation Via Regulation of Centrosome Localization and ECT2 Degradation (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_5279;
The translocation of AURKA, which is originally restricted to centrosome relied on ?-tubulin interaction during nuclear polarization, was to directly degrade ECT2 at the anterior end of the protrusive nucleus for final nuclear expulsion. Our findings reveal a previously unrecognized localization and role of Aurora kinases in terminal erythroid differentiation and provide new mechanistic insights into erythroblast enucleation.
- |||||||||| AT9283 / Otsuka
Journal, PD(L)-1 Biomarker, IO biomarker: Multifaceted Effects of Kinase Inhibitors on Pancreatic Cancer Cells Reveals Pivotal Entities with Therapeutic Implications. (Pubmed Central) - Jun 28, 2023
To this end, we screened a library of kinase inhibitors in the PDAC cell lines PANC-1 and BxPC-3 and identified two highly potent molecules: Aurora kinase inhibitor AT 9283 (AT) and EGFR kinase inhibitor WZ 3146 (WZ)...Furthermore, combination therapy outcomes with gemcitabine/platinum drugs may also be more effective due to an increase in the NADH dehydrogenase complex...Additionally, novel therapy options, such as vimentin-antibody--drug conjugates, could be explored. Therefore, future studies with the two kinases as monotherapy/combination therapy are warranted.
- |||||||||| AT9283 / Otsuka, Isentress (raltegravir) / Merck (MSD)
Journal: PERV induces CXCL10 in human monocytes and monocyte-derived primary cells. (Pubmed Central) - Nov 18, 2022
The combination of Aurora kinase inhibition with LPCAT1 inhibition may exert promising synergistic effects on GBM. Our findings highlight PERVs as inducers of the pro-inflammatory chemokine CXCL10 and other innate immune responses in human monocytes and derived cells with potential implications in the context of xenotransplantation.
- |||||||||| Jakafi (ruxolitinib) / Novartis, Incyte, AT9283 / Otsuka, givinostat (ITF2357) / Italfarmaco
Drug-Induced Hypertension in Classical Philadelphia-Negative Myeloproliferative Neoplasms (MPNs): Systematic Review () - Sep 22, 2022 - Abstract #SOHO2022SOHO_647;
Ruxolitinib’s effect (RUX) on systolic (SBP)/diastolic (DBP) blood pressure is controversial: one study reported no effect on SBP/DBP, whereas in another SBP but not DBP increased...Anagrelide caused DI-HTN as AE in 9 essential thrombocythemia (ET) subjects, however, hydroxyurea caused DI-HTN in 1 of 146 patients... RUX (alone/in combination with decitabine/danazol), anagrelide, AT9283, and givinostat can cause DI-HTN in classical Philadelphia-negative MPNs.
- |||||||||| AT9283 / Otsuka
Journal: Inhibitors targeting the autophosphorylation of serine/threonine kinase of Streptococcus suis show potent antimicrobial activity. (Pubmed Central) - Sep 21, 2022
A series of inhibitors against ssSTK are identified from a commercial kinase inhibitors library, including Staurosporine, K252a, AT9283, and APY29...Additionally, it was predicted by molecular docking that these inhibitors could interact with ssSTK. Collectively, our data illustrated the essential roles of ssSTK autophosphorylation in the physiology and pathogenicity of S. suis and consider these inhibitors as promising antimicrobial lead compounds.
- |||||||||| decernotinib (VX-509) / Vertex
Journal: Topical VX-509 Attenuates Psoriatic Inflammation Through the STAT3/FABP5 Pathway in Keratinocytes. (Pubmed Central) - Aug 11, 2022
Collectively, our data illustrated the essential roles of ssSTK autophosphorylation in the physiology and pathogenicity of S. suis and consider these inhibitors as promising antimicrobial lead compounds. This study demonstrated administration of VX-509 is a potential promising topical drug for treatment of psoriasis, FABP5 is a critical targeted molecule in psoriasis therapy.
- |||||||||| Journal: Phenotypic Screening for Small Molecules that Protect β-Cells from Glucolipotoxicity. (Pubmed Central) - May 25, 2022
These 10 compounds decreased markers of glucolipotoxicity including caspase activation, mitochondrial depolarization, and increased calcium flux. Together, these results provide a path forward toward identifying novel treatments to preserve β-cell viability in the face of glucolipotoxicity.
- |||||||||| AT9283 / Otsuka
Journal: Drug repositioning of COVID-19 based on mixed graph network and ion channel. (Pubmed Central) - Apr 5, 2022
It can predict the drug-target affinity more accurately. According to the prediction results of drug-target affinity of SARS-CoV-2 ion channel targets, seven kinds of small molecule drugs acting on five ion channel targets were obtained, namely SCH-47112, Dehydroaltenusin, alternariol 5-o-sulfate, LPA1 antagonist 1, alternariol, butin, and AT-9283.These drugs provide a reference for drug repositioning and precise treatment of COVID-19.
- |||||||||| AT9283 / Otsuka, alvocidib (DSP-2033) / Sumitomo Dainippon, Daurismo (glasdegib) / Pfizer
Case study of single-cell protein activity-based drug prediction and validation for precision treatment of cholangiocarcinoma (Section 28) - Mar 9, 2022 - Abstract #AACR2022AACR_5793;
Both of these drugs significantly extended survival time by Kaplan-Meier regression (p=0.001 and p=0.03, respectively). Furthermore, scRNASeq data of drug-treated PDXs showed that Dacinostat uniformly depleted all three tumor sub-populations compared to Vehicle control, whereas one of the tumor sub-clusters was resistant to Plicamycin, consistent with single-cell drug sensitivity predicted by OTr.Given the in vivo activity of these two drugs in inhibiting tumor growth, and the effectiveness of Dacinostat across observed tumor cell phenotypes, as well as the high immune infiltration of this CCA sample, these drugs may be translated into pre-clinical and clinical trials alone and in combination with checkpoint immunotherapy.
- |||||||||| AT9283 / Otsuka
Journal: AT9283 exhibits antiproliferative effect on tyrosine kinase inhibitor‑sensitive and ‑resistant chronic myeloid leukemia cells by inhibition of Aurora A and Aurora B. (Pubmed Central) - Jul 8, 2021
Imatinib is the gold standard in the conventional treatment of chronic myeloid leukemia (CML)...To overcome this resistance, second‑generation (dasatinib, nilotinib, and bosutinib) and third‑generation (ponatinib) tyrosine kinase inhibitors (TKIs) have been developed and have been shown to be effective against refractory CML...In addition, we found that AMG900, a selective Aurora A and Aurora B inhibitor, increased the G2/M phase cell population and induced apoptosis via inhibition of Aurora A and Aurora B in both TKI‑sensitive and TKI‑resistant CML cells. Our studies show that Aurora A and Aurora B are promising therapeutic targets for TKI‑sensitive and TKI‑resistant CML, and AT9283 may have potential clinical applications for the treatment of TKI‑resistant CML patients.
- |||||||||| AT9283 / Otsuka, Enpaxiq (pacritinib) / CTI BioPharma
Journal: A novel human colon signet-ring cell carcinoma organoid line: establishment, characterization and application. (Pubmed Central) - Feb 7, 2021
An in vitro drug screening found that AT9283 and Pacritinib could be effective JAK2 inhibitors, which was consistent with the in vivo xenograft response. We report, for the first time, the establishment of an SRCC organoid line allowing in-depth study of SRCC biology, as well as a strategy to assess in vitro drug testing in a personalized fashion.
- |||||||||| Journal: A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein. (Pubmed Central) - Mar 4, 2020
We used the CellTiter-Glo viability assay to test library compounds against parental KB-3-1 human cervical adenocarcinoma cells and the colchicine-selected subline KB-8-5-11 that overexpresses P-gp...ABCG2 was also found to confer high levels of resistance to AT9283, GSK-690693, and gedatolisib, whereas ispinesib, AT7519, and KW-2478 were weaker substrates...Of the 10,804 compounds screened, a total of 90 substrates were identified of which 55 were novel. P-gp expression may adversely affect the oral bioavailability or brain penetration of these compounds.
- |||||||||| AT9283 / Otsuka
Journal: Identification of Candidate Genes and Therapeutic Agents for Light Chain Amyloidosis Based on Bioinformatics Approach. (Pubmed Central) - Feb 27, 2020
More importantly, we identified the small molecular agents (AT-9283, Ritonavir and PKC beta-inhibitor) as the potential drugs for AL amyloidosis. Using bioinformatics approach, we have identified candidate genes and pathways in AL amyloidosis, which can extend our understanding of the cause and molecular mechanisms, and these crucial genes and pathways could act as biomarkers and therapeutic targets for AL amyloidosis.
- |||||||||| AT9283 / Otsuka
Trial completion: CRUK-CR0708-11: AT9283 in Children and Adolescents With Relapsed and Refractory Solid Tumors (clinicaltrials.gov) - Nov 29, 2019
P1, N=33, Completed,
Using bioinformatics approach, we have identified candidate genes and pathways in AL amyloidosis, which can extend our understanding of the cause and molecular mechanisms, and these crucial genes and pathways could act as biomarkers and therapeutic targets for AL amyloidosis. Active, not recruiting --> Completed
- |||||||||| tozasertib (MK-0457) / Vertex, Merck (MSD)
Journal: RIPK1-dependent cell death: a novel target of the Aurora kinase inhibitor Tozasertib (VX-680). (Pubmed Central) - Sep 18, 2019
The potency ranking of the newly derived Tozasertib analogues and their specificity profile, as observed in cellular assays, coincide with ADP-Glo recombinant kinase activity assays. Overall, we show that Tozasertib not only targets Aurora kinases but also RIPK1 independently, and that we could generate analogues with increased selectivity to RIPK1 or Aurora kinases, respectively.
- |||||||||| AT9283 / Otsuka
Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date: CRUK-CR0708-11: AT9283 in Children and Adolescents With Relapsed and Refractory Solid Tumors (clinicaltrials.gov) - Aug 24, 2018
P1, N=33, Active, not recruiting,
Overall, we show that Tozasertib not only targets Aurora kinases but also RIPK1 independently, and that we could generate analogues with increased selectivity to RIPK1 or Aurora kinases, respectively. Completed --> Active, not recruiting | N=24 --> 33 | Trial completion date: Dec 2012 --> Dec 2018 | Trial primary completion date: Dec 2012 --> Jan 2016
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