orantinib (TSU-68) / Otsuka, Pfizer - LARVOL DELTA

Cell Signalling Pathways Involved in Interleukin-33 Release by Human Primary Keratinocytes. (ESDR 2024) - "PDGFR antagonists Crenolanib and Orantinib significantly but only slightly reduced IL-33 release by NHEK. In contrast, the pan-RTK inhibitor Nintedanib led to more robust suppression, reducing IL-33 release by 50% (P < 0.001)...Interestingly, we found that recombinant EGF significantly suppressed and the EGFR inhibitor cetuximab augmented FSA-induced IL-33 release...RTK and GPCR are known to be closely intertwined and can transactivate each other. We conclude that release of IL-33 by Sbi involves a non-EGFR RTK/GPCR pathway, and that EGF attenuates this Th2 immune response in skin cells in vitro."

Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • AKT1 • IL33 • PDGFRB

BIN1 deficiency enhances ULK3-dependent autophagic flux and reduces dendritic size in mouse hippocampal neurons. (PubMed, Autophagy) - "Unexpectedly, Bin1 knockdown led to concurrent activation of both macroautophagy/autophagy and MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1). Autophagy inhibition with the lysosome inhibitor chloroquine effectively mitigated the Bin1 knockdown-induced dendritic regression...Reducing ULK3 activity with SU6668, a receptor tyrosine kinase inhibitor, or decreasing neuronal ULK3 expression through AAV-mediated RNAi, significantly attenuated Bin1 knockdown-induced hippocampal volume loss and spatial memory decline. In Alzheimer disease patients, the major neuronal isoform of BIN1 is specifically reduced. Our work suggests this reduction is probably an important molecular event that increases the autophagy level, which might subsequently promote brain atrophy and cognitive impairment through reducing dendritic structures, and ULK3 is a potential interventional target for relieving these detrimental effects."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • ULK3

Biomimetic nanocomplex based corneal neovascularization theranostics. (PubMed, J Control Release) - "Furthermore, SU6668 could inhibit the expression of heat shock protein 70, promoting the cell death induced by photothermal effect. In conclusion, the combination of photothermal and chemotherapy drugs provides a novel, effective and safe approach for the treatment of CNV."

Journal • Ophthalmology

A SU6668 pure nanoparticle-based eyedrops: toward its high drug Accumulation and Long-time treatment for corneal neovascularization. (PubMed, J Nanobiotechnology) - "Meanwhile, drug safety test confirmed that T-MNS did not cause any damage to cornea, retina and other eye tissues. In conclusion, the T-MNS eye drop had the potential to treat CNV effectively and safely in a low dosing frequency, which broke new ground for CNV theranostics."

Journal • Corneal Abrasion • Ophthalmology

Transarterial chemoembolization with or without multikinase inhibitors for patients with unresectable hepatocellular carcinoma: a systematic review and meta-analysis of randomized controlled trials. (PubMed, Front Oncol) - "A total of 10 RCTs comprising 2837 patients receiving combination therapy (TACE plus sorafenib, brivanib, orantinib or apatinib) were included. TACE+MKI combination therapy improved TTP and ORR but not OS and PFS in patients with unresectable HCC. Further high-quality trials are needed to verify these clinical benefits, and our findings could be very informative for future trial design."

Retrospective data • Review • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

A new molecular subclassification and in silico predictions for diagnosis and prognosis of papillary thyroid cancer by alternative splicing profile. (PubMed, Front Pharmacol) - "Finally, three compounds (orantinib, tyrphostin-AG-1295 and AG-370) were discovered to be the potential therapeutic agents. Overall, the six DEAS events are not only potential biomarkers for precise diagnosis of PTC, but also the probable prognostic predictors. This research would be expected to highlight the effect of AS events on PTC characterization and also provide new insights into refining precise subclassification and improving medical therapy for PTC patients."

IO biomarker • Journal • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma

Structure-based virtual screening of chemical libraries as potential MELK inhibitors and their therapeutic evaluation against breast cancer. (PubMed, Chem Biol Interact) - "We performed molecular docking for virtual screening of chemical libraries (phytochemicals/synthetic drugs) against MELK protein structure and identified 8 phytoconstituents (isoxanthorin, emodin, gamma-coniceine, quercetin, tenuazonic acid, isoliquiritigenin, kaempferol, and Nobiletin) and 8 synthetic drugs (tetrahydrofolic acid, alfuzosin, lansoprazole, ketorolac, ketoprofen, variolin B, orantinib, and firestein) as potential hits interacting with the active site residues of MELK based on bound poses, hydrogen bond, hydrophobic interactions and MM/GBSA binding free energies. Treatment with both molecules downregulated MELK expression, induced cell cycle arrest, accumulated DNA damage and enhanced apoptosis. The study identified isoliquiritigenin and emodin as potential MELK inhibitors and provides a basis for subsequent experimental validation and drug development against cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MELK

Platelet-derived growth factor (PDGF)-BB regulates the airway tone via activation of MAP2K, thromboxane, actin polymerisation and Ca-sensitisation. (PubMed, Respir Res) - "PDGFR regulates the airway tone. In PCLS from GPs, this regulatory mechanism depends on the β-subunit. Hence, PDGFR-inhibition may not only represent a target to improve chronic airway disease such as IPF, but may also provide acute bronchodilation in asthma. Since asthma therapy uses topical application. This is even more relevant, as nebulisation of imatinib also appears to be effective."

Journal • Asthma • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Pharmacological PDGFRβ inhibitors imatinib and sunitinib cause human brain pericyte death in vitro. (PubMed, Toxicol Appl Pharmacol) - "We treated human brain vascular pericytes, which express PDGFRβ, with three receptor tyrosine kinase inhibitors: imatinib, sunitinib and orantinib. Overall, we found that receptor tyrosine kinase inhibitors that block PDGFRβ phosphorylation cause healthy pericytes to die in vitro. While useful in cancer to limit tumor growth, these agents could impair healthy brain pericyte survival and impact brain function."

Journal • Preclinical • Oncology • PDGFRB

Drug Repurposing for COVID-19 Treatment by Integrating Network Pharmacology and Transcriptomics. (PubMed, Pharmaceutics) - "We identified 18 individual drug candidates including nicardipine, orantinib, tipifarnib and promethazine which have not previously been proposed as possible treatments for COVID-19. Additionally, 30 synergistic drug pairs were ultimately recommended including fostamatinib plus tretinoin and orantinib plus valproic acid. Differential expression genes of most repurposing drugs were enriched significantly in B cells. The findings may potentially accelerate the discovery and establishment of an effective therapeutic treatment plan for COVID-19 patients."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

PRE-TREATMENT MUCOSAL INFLAMMATORY AND WOUND HEALING GENE PROGRAMS REVEAL MECHANISMS ASSOCIATED WITH FUTURE STRICTURING BEHAVIOR DURING FIVE YEAR FOLLOW-UP IN PEDIATRIC CROHN’S DISEASE (DDW 2020) - "We further define small molecules targeting macrophage and fibroblast activation, and angiogenesis, which may reverse the stricturing gene signature including ephrin inhibitors, eicosatetraynoic acid (cyclooxygenase/lipoxygenase inhibitor), orantinib (PDGFR inhibitor), and PT-630 (fibroblast activation protein inhibitor, Fig... An ileal gene program for macrophage and fibroblast activation is linked to future stricturing complications in treatment naïve pediatric CD, and may inform small molecule therapeutic approaches."

Clinical • Crohn's disease • Fibrosis • Gastroenterology • Immunology • Inflammatory Bowel Disease • Pediatrics • COL1A2 • FAP • GS • PDPN

Establishment and characterization of NCC-ASPS1-C1: a novel patient-derived cell line of alveolar soft-part sarcoma. (PubMed, Hum Cell) - "We found that the MET inhibitor tivantinib and multi-kinase inhibitor orantinib inhibited the proliferation of NCC-ASPS1-C1 cells. The clinical utility and molecular mechanisms of antitumor effects of these drugs are worth investigating in the further studies, and NCC-ASPS1-C1 cells will be a useful tool for the in vitro study of alveolar soft-part sarcoma."

Journal • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

A multicenter phase II study of TSU-68, an oral multiple tyrosine kinase inhibitor, in combination with docetaxel in metastatic breast cancer patients with anthracycline resistance (Breast Cancer) - P2, N=19; JPRN-JapicCTI-101178; OR in 21.1% & clinical benefits in 42.1% of the pts, respectively (CR=1, PR=3 & SD=4, for at least 24 wks); mTTP=148 days, & mOS=579 days

P2 data • Breast Cancer • Oncology

Phase I clinical study of the angiogenesis inhibitor TSU-68 combined with carboplatin and paclitaxel in chemotherapy-naive patients with advanced non-small cell lung cancer (J Thorac Oncol) - P1, N=37; No dose-limiting toxicities were observed with TSU-68 at the 200 mg twice a day dose level; At 400 mg twice a day, one of six pts experienced a dose-limiting toxicity (anorexia of grade 3) during the first cycle; The 400 mg twice a day dose level was determined to be the recommended dose, & a total of 34 pts were treated at this dose; The ORR was 39.4%, & median PFS was 5.6 months; Coadministration of TSU-68, carboplatin, & paclitaxel had no substantial impact on the pharmacokinetics of these drugs

P1 data • Non Small Cell Lung Cancer • Oncology

A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer (ASCO-GI 2013) - P2, N=105; JapicCTI-111403; " TSU-68 plus SOX showed a favorable safety profile. However, TSU-68 did not have a synergistic effect on the efficacy of SOX. Baseline serum IL-6 levels could be prognostic factors for TSU-68 efficacy."

P2 data • Oncology

Taiho Pharmaceutical announces termination of phase III clinical trial of the angiogenesis inhibitor TSU-68 (orantinib) in patients with hepatocellular carcinoma (Taiho Press Release) - P3, N=880; ORIENTAL (NCT01465464); Sponsor: Taiho; "An independent data monitoring committee conducted an interim analysis, the results of which indicated that the pre-determined standard related to the primary endpoint of overall survival was not met, and they therefore recommended that the trial be terminated. Based on this recommendation, Taiho Pharmaceutical made the decision to terminate the trial and communicated to the relevant regulatory authorities as well as all the principal investigators that the trial had been terminated. Detailed results from this trial will be announced at an appropriate medical conference in the future."

Anticipated P3 data • Trial termination • Hepatocellular Cancer • Oncology

Randomized phase II study of S-1/CDDP plus TSU-68 versus S-1/CDDP in patients with advanced gastric cancer (ASCO-GI 2013) - P2, N=93; JapicCTI-101327; "TSU-68 plus S-1/CDDP therapy did not prolong PFS of patients with advanced GC as compared with S-1/CDDP."

P2 data • Oncology

Phase I study of safety, pharmacokinetics, and efficacy of TSU-68 plus S-1 combination in patients with advanced hepatocellular carcinoma (ASCO-GI 2013) - P1, N=18; Japic CTI-121970; "TSU-68 plus S-1 combination was well tolerated and had favorable efficacy in patients with advanced HCC, and we recommend treatment with 400 mg/day TSU-68 and 100 mg/m2 S-1 for 4 weeks followed by 2-week rest in these patients."

P1 data • Oncology

A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer (Invest New Drugs) - P2, N=105; "The median PFS was 7.0 months in the TSU-68 + SOX group (hazard ratio [HR], 1.057) and 7.2 months in the SOX group (p = 0.8401). The most frequent grade 3 and 4 adverse events were thrombocytopenia (9.6 % [TSU-68 + SOX] vs. 26.4 % [SOX]), neutropenia (13.5 % [TSU-68 + SOX] vs. 15.1 % [SOX]), and anemia (3.8 % [TSU-68 + SOX] vs. 13.2 % [SOX])."

P2 data • Colorectal Cancer • Oncology

"New: Orantinib vs placebo combined with TACE for unresectable #hepatocellularcarcinoma (ORIENTAL trial) https://t.co/6DP1AUrUoE #livercancer" (@LancetGastroHep)

Clinical • Biosimilar • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Subgroup analysis of efficacy and safety of orantinib in combination with TACE in Japanese HCC patients in a randomized phase III trial (ORIENTAL). (PubMed, Med Oncol) - "No significant differences were observed in the OS and TTTF though the TTP was significantly improved in the orantinib arm. The OS and TTTF showed a tendency to be prolonged following orantinib treatment of Japanese HCC patients with BCLC-B in the ORIENTAL study."

Clinical • Combination therapy • Journal • P3 data

Characterization of protein kinase ULK3 regulation by phosphorylation and inhibition by small molecule SU6668. (PubMed, Biochemistry) - "We show that a small molecular weight inhibitor SU6668, designed as an ATP competitive inhibitor for tyrosine kinases, binds in the ATP pocket of ULK3, yet it inhibits ULK3 kinase activity in a partially ATP non-competitive manner. Finally, we demonstrate that ULK3 kinase domain, annotated in silico, is not sufficient for its kinase activity, and additional amino acids in the 271-300 region are required."

Journal