AT9283 / Otsuka - LARVOL DELTA

Repurposed AT9283 triggers anti-tumoral effects by targeting MKK3 oncogenic functions in Colorectal Cancer. (PubMed, J Exp Clin Cancer Res) - "Overall, we demonstrated that the anti-tumoral effects triggered by AT9283 treatment recapitulated the MKK3 depletion effects in all tested CRC models in vitro and in vivo, suggesting that AT9283 is a repurposed drug. According to its good tolerance when tested with primary colonocytes (CCD-18CO), AT9283 is a promising drug for the development of novel therapeutic strategies to target MKK3 oncogenic functions in late-stage and metastatic CRC patients."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • AURKA • MAP2K3

Regulation of Cell Cycle Progression through RB Phosphorylation by Nilotinib and AT-9283 in Human Melanoma A375P Cells. (PubMed, Int J Mol Sci) - "In this study, we delved into the underlying mechanisms of specific BCR-ABL tyrosine kinase inhibitors (imatinib, nilotinib, ZM-306416, and AT-9283) in human melanoma A375P cells. Consequently, the expression of the E2F target genes (CCNA2, CCNE1, POLA1, and TK-1) was markedly suppressed in nilotinib and AT9283-treated A375P cells. In summary, our findings suggest that BCR-ABL tyrosine kinase inhibitors may regulate the G1-to-S transition in human melanoma A375P cells by modulating the RB-E2F complex."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Melanoma • Oncology • Solid Tumor • ABL1 • BCR • CCNA2 • CCNE1 • POLA1

DLGAP5 promotes lung adenocarcinoma growth via upregulating PLK1 and serves as a therapeutic target. (PubMed, J Transl Med) - "Our research has demonstrated that DLGAP5 is upregulated in LUAD and exhibits a strong correlation with unfavorable prognosis. Furthermore, DLGAP5 assumes a significant function in the regulation of tumor immunity and treatment outcome of immune checkpoint inhibitors. Of note, we found that DLGAP5 promotes cell proliferation of LUAD via upregulating PLK1. Targeting DLGAP5 by AT9283, our newly identified DLGAP5 inhibitor, suppresses LUAD growth. DLGAP5 may become a promising prognostic biomarker and therapeutic target for patients with LUAD."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PLK1

The Aurora kinase inhibitor AT9283 inhibits Burkitt lymphoma growth by regulating Warburg effect. (PubMed, PeerJ) - "The reversal of the Warburg effect in BL cells and the subsequent inhibition of cell proliferation and induction of apoptosis were observed by targeting Aurora A and Aurora B with AT9283. This finding may present new therapeutic options and targets for BL."

Journal • Burkitt Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • HIF1A • HK2 • LDHA • MYC • PKM

AURKA Kinase Controls Erythroblast Enucleation Via Regulation of Centrosome Localization and ECT2 Degradation (ASH 2023) - "Treatment of erythroblasts with MLN8237 (Aliseritib, AURKA selective inhibitor), AZD1152(Barasertib, AURKB selective inhibitor), or AT9283 (AURKA and AURKB inhibitor) dramatically blocked enucleation in a dose-dependent manner. The translocation of AURKA, which is originally restricted to centrosome relied on γ-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."

AURKA • AURKB • PLK4

HIGH-THROUGHPUT AND HIGH-CONTENT DRUG SCREENING ON A LARGE-SCALE PATIENT-DERIVED HIGH-RISK COLORECTAL ADENOMA ORGANOID PLATFORM (UEGW 2023) - "Four drugs including metformin, BMS754807, Panobinostat, and AT9283 were screened out as potential hits with generally consistent inhibitory efficacy on HRCA-PDOs. This study established a promising HRCA-PDO biobank and conducted the first high-throughput and high-content HRCA drug screening in order to shed light on prevention of colorectal cancer."

Clinical • Colorectal Cancer • Gastrointestinal Cancer • MYC • WNT3

Establishment of a large-scale patient-derived high-risk colorectal adenoma organoid biobank for high-throughput and high-content drug screening. (PubMed, BMC Med) - "This study established a promising HRCA-PDO biobank and conducted the first high-throughput and high-content HRCA drug screening in order to shed light on the prevention of colorectal cancer."

Journal • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MYC • WNT3

The Comprehensive Analysis of m6A-Associated Anoikis Genes in Low-Grade Gliomas. (PubMed, Brain Sci) - "AT.9283, EXEL.2280, Gilteritinib, and Pracinostat had the largest correlation (absolute value) with a risk score. Four risk model genes (mRNAs), 12 miRNAs, and 21 lncRNAs formed an mRNA-miRNA-lncRNA network, containing HOXA10-hsa-miR-129-5p-LINC00689 and KIF18A-hsa-miR-221-3p-DANCR. Through bioinformatics, we constructed a prognostic model of m6A-associated anoikis genes in LGG, providing new ideas for research related to the prognosis and treatment of LGG."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • ANXA5 • BRCA1 • CD4 • DANCR • KIF18A • MIR129 • MIR221

Overfit deep neural network for predicting drug-target interactions. (PubMed, iScience) - "Performance of OverfitDTI on three public datasets showed that the overfit DNN models fit the nonlinear relationship with high accuracy. We identified fifteen compounds that interacted with TEK, a receptor tyrosine kinase contributing to vascular homeostasis, and the predicted AT9283 and dorsomorphin were experimentally demonstrated as inhibitors of TEK in human umbilical vein endothelial cells (HUVECs)."

Journal

Multifaceted Effects of Kinase Inhibitors on Pancreatic Cancer Cells Reveals Pivotal Entities with Therapeutic Implications. (PubMed, Biomedicines) - "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."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BCL2 • CASP3 • CASP7 • KRAS • VIM

The inhibition of Aurora A kinase regulates phospholipid remodeling by upregulating LPCAT1 in glioblastoma. (PubMed, Neoplasma) - "Notably, the inhibition of Aurora A kinase by shRNA knockdown and treatment with Aurora A kinase inhibitors such as Alisertib, AMG900, or AT9283 upregulated LPCAT1 mRNA and protein expression in vitro. Aurora A kinase inhibition increased LPCAT1 expression and suppressed GBM cell proliferation. The combination of Aurora kinase inhibition with LPCAT1 inhibition may exert promising synergistic effects on GBM."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Metabolic Disorders • Oncology • Solid Tumor • AURKA • LPCAT1 • LPCAT4

Drug-Induced Hypertension in Classical Philadelphia-Negative Myeloproliferative Neoplasms (MPNs): Systematic Review (SOHO 2022) - "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."

Review • Acute Myelogenous Leukemia • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera

Novel Drugs to Target JAK2 Rearrangements in Pediatric Acute Lymphoblastic Leukemia (ASH 2022) - "After 48h monotherapy treatment by CHZ868, we detected decreased cell viability (20-75% at IC50), which increased in the combination with dexamethasone...Importantly, combination of BIBF1120 and CHZ868 showed a synergistic effect (-45%, at IC50)...Indeed, active caspase 3 increased after ruxolitinib and chloroquine (autophagy inhibitor) combination (+20% vs ruxolitinib alone, p<0.01)...Instead, AT9283 (p<0.001 vs LCLs), Fedratinib (p<0.01 vs LCLs) and Gandotinib (p<0.05 vs LCLs) were found to be potent, specific, and non-toxic JAK2 inhibitors. Additionally, this extended screening led us to identify drugs, not belonging to JAK inhibitors, specific and non-toxic for rearranged JAK2 cohort, such as Birinapant (Smac mimetic), JQ1 (BRD4 inhibitor), Fludarabine (Chemotherapy) among the others. CHZ868 is a promising drug for the treatment of JAK2 fusions. Further studies will focus on effective and specific novel drugs found to be highly effective and specific on..."

Clinical • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • ATF7IP • BRD4 • CASP3 • CD19 • CRLF2 • MME • P2RY8 • PAX5 • PDPK1 • STAT3 • STAT5 • ZEB2

PERV induces CXCL10 in human monocytes and monocyte-derived primary cells. (PubMed, Intervirology) - "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."

Journal • Infectious Disease • Transplantation • CXCL10 • IFNB1

AT9283, 1-Cyclopropyl-3-(3-(5-(Morpholinomethyl)-1H-Benzo[d]Imidazole-2-yl)-1H-Pyrazol-4-yl) Urea, Inhibits Syk to Suppress Mast Cell-Mediated Allergic Response. (PubMed, Biomol Ther (Seoul)) - "34 mg/kg, p.o.). These findings suggest that AT9283 has potential to use as a new drug for alleviating the symptoms of IgE-mediated allergic disorders."

Journal • Allergy • Immunology • Oncology • IL4 • SYK • TNFA

MDS-053 Drug-Induced Hypertension in Classical Philadelphia-Negative Myeloproliferative Neoplasms (MPNs): Systematic Review. (PubMed, Clin Lymphoma Myeloma Leuk) - "RUX (alone/in combination with decitabine/danazol), anagrelide, AT9283, and givinostat can cause DI-HTN in classical Philadelphia-negative MPNs."

Journal • Retrospective data • Review • Acute Myelogenous Leukemia • Cardiovascular • Essential Thrombocythemia • Hypertension • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • Thrombocytosis

Inhibitors targeting the autophosphorylation of serine/threonine kinase of Streptococcus suis show potent antimicrobial activity. (PubMed, Front Microbiol) - "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."

Journal • Infectious Disease

Topical VX-509 Attenuates Psoriatic Inflammation Through the STAT3/FABP5 Pathway in Keratinocytes. (PubMed, Pharmacol Res) - "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 • Dermatology • Immunology • Inflammation • Metabolic Disorders • Psoriasis • FABP5 • IL22 • STAT3

Phenotypic Screening for Small Molecules that Protect β-Cells from Glucolipotoxicity. (PubMed, ACS Chem Biol) - "Validation studies in dissociated human islets identified 10 of the 17 compounds, namely, KD025, ETP-45658, BMS-536924, AT-9283, PF-03814735, torin-2, AZD5438, CP-640186, ETP-46464, and GSK2126458 that reduced glucolipotoxicity-induced β-cell death. 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."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Neuroendocrine Tumor • Obesity • Solid Tumor • Type 2 Diabetes Mellitus

Case study of single-cell protein activity-based drug prediction and validation for precision treatment of cholangiocarcinoma (AACR 2022) - "Consensus OTar/OTr drug prediction analysis on both scRNASeq tumor cells and bulk RNA-Seq of an engrafted PDX model from resected tumor at the time of biopsy ranked Glasdegib, Plicamycin, Flavopiridol, AT9283, and Dacinostat as the top 5 drugs with best overall tumor cell coverage. 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..."

Clinical • IO biomarker • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS • MYC • TNFA

Inhibition of novel kinase MAP3K19 reverses EMT and kills triple negative breast cancer cell lines (AACR 2022) - "Treatment with AT-9283, a more specific MAP3K19 inhibitor, resulted in cellular death and reversal in EMT gene signature by qPCR. Future directions for this project involve genetic knock-down and overexpression of MAP3K19 to evaluate its roles in biology and its signaling mechanisms."

Preclinical • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • ITK

Drug repositioning of COVID-19 based on mixed graph network and ion channel. (PubMed, Math Biosci Eng) - "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."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Production of NOS2 and inflammatory cytokines is reduced by selected protein kinase inhibitors with partial repolarization of HL-60 derived and human blood macrophages. (PubMed, Heliyon) - "Phagocytic capacity of HL-60 derived macrophages was higher in M1 macrophages and decreased by trametinib and a p38 inhibitor, while in human blood macrophages, where AT 9283, a JAK/STAT inhibitor also caused a significant decrease in M1 polarized macrophages, no difference was observed between M1 and M2 macrophages. Our results suggest that the repolarization of macrophages cannot be achieved by inhibiting their signaling pathways; nevertheless, the expression of certain polarization markers was decreased, therefore a "depolarization" could be observed both in M1 and M2 polarized cells. Selected protein kinase inhibitors of M1 polarization, decreasing NOS 2 and inflammatory cytokines may be potential candidates for therapeutical trials against inflammatory diseases."

Journal • Immune Modulation • Inflammation • AMPK • CXCL8 • IFNG • IL4 • MRC1 • NOS2 • TNFA

Integrated bioinformatic analysis reveals the underlying molecular mechanism of and potential drugs for pulmonary arterial hypertension. (PubMed, Aging (Albany NY)) - "Moreover, to repurpose known and therapeutic drugs, the CMap database was retrieved, and nine candidate compounds (lypressin, ruxolitinib, triclabendazole, L-BSO, tiaprofenic acid, AT-9283, QL-X-138, huperzine-a, and L-741742) with a high level of confidence were obtained. A certain concentration of ruxolitinib could inhibit the proliferation and migration of rat pulmonary artery smooth muscle cells (rPASMCs) in vitro. Together, these analyses principally identified CSF3R, NT5E, ANGPT2, FGF7 and CXCL9 as candidate biomarkers of PAH, and ruxolitinib might exert promising therapeutic action for PAH."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CD73 • CSF3R • CXCL9 • JAK1 • JAK2 • JAK3 • NT5E • TYK2

AT9283 exhibits antiproliferative effect on tyrosine kinase inhibitor‑sensitive and ‑resistant chronic myeloid leukemia cells by inhibition of Aurora A and Aurora B. (PubMed, Oncol Rep) - "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."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • CASP3 • STAT3