amuvatinib (MP470) / Otsuka - LARVOL DELTA

Unveiling the Role of SLC6A17 in Lung Adenocarcinoma: Prognosis, Pathways, and Therapeutic Implications. (PubMed, Curr Med Chem) - "These findings suggest that SLC6A17 indicates the potential of a potential prognostic biomarker and immunotherapeutic target for patients with LUAD."

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

Emerging AXL Inhibitors in Oncology: Chemical and Biological Advances in Targeted Cancer Therapy. (PubMed, Anticancer Agents Med Chem) - "In conclusion, developing AXL inhibitors represents a promising avenue for improving cancer treatment outcomes. Continued research efforts are essential to overcome the existing challenges and translate these compounds into effective clinical therapies."

Journal • Gene Therapies • Oncology

System biology analysis of miRNA-gene interaction network reveals novel drug targets in breast cancer. (PubMed, Nucleosides Nucleotides Nucleic Acids) - "By searching for potential drugs in Drugbank database, we have identified four candidates (phenethyl isothiocyanate, amuvatinib, theophylline, trifluridine) for targeting these genes. In conclusion, we believe that these drugs and their analogs could be used in the targeted therapy of breast cancer in the future."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • MIR127 • PGR

Advancing lung adenocarcinoma treatment: Establishing KRAS-driven organoids for drug screening (ELCC 2024) - "Our findings reveal that targeted drugs Amuvatinib, Midostaurin, and Selumetinib are selectively active against KRASG12V-driven LADC organoids. Notably, a synergistic effect was observed when combining these active targeted agents with the epigenetic drug Decitabine...We identified promising compounds and combinations that show potential for effectively combating KRASG12V-driven LADC. These findings highlight the significance of our model in targeted drug discovery and advancing personalized therapeutic approaches for patients with this aggressive form of lung cancer."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • NKX2-1 • TTF1

Identification of a cancer-associated fibroblast classifier for predicting prognosis and therapeutic response in lung squamous cell carcinoma. (PubMed, Medicine (Baltimore)) - "In silico drug screening identified 6 effective compounds for high-risk CAFs-related LUSC: TAK-715, GW 441756, OSU-03012, MP470, FH535, and KIN001-266. Additionally, search tool for interaction of chemicals database highlighted PI3K-Akt signaling as a potential target pathway for high-risk CAFs-related LUSC. Overall, our findings provide a molecular classifier for high-risk CAFs-related LUSC and suggest that treatment with PI3K-Akt signaling inhibitors could benefit these patients."

IO biomarker • Journal • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma • CAFs • KLF10 • PDGFA • SERPINE1 • SMAD7

Pharmacological profiling identifies divergent chemosensitivities of differentiating and maturing iPSC-derived human cortical neuron populations. (PubMed, FEBS J) - "Ponatinib and amuvatinib were neuroinhibitory for differentiating and maturing neurons, respectively. Amuvatinib treatment of maturing neuronal cultures significantly reduced pAXL levels. These studies indicate that neuronal developmental states may exhibit unique chemosensitivities and that drugs may have different neuro-inhibitory effects depending upon the developmental stage of the neuronal population."

Journal • AXL • GAS6

Probing the Potential of Defense Response-Associated Genes for Predicting the Progression, Prognosis, and Immune Microenvironment of Osteosarcoma. (PubMed, Cancers (Basel)) - "This study elucidated the role and mechanism of BNIP3, PTGIS, and ZYX in OS progression and was well verified by the experimental results, enabling reliable prognostic means and treatment strategies to be proposed for OS patients."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CD8

Amuvatinib Blocks SARS-CoV-2 Infection at the Entry Step of the Viral Life Cycle. (PubMed, Microbiol Spectr) - "In the present study, we investigated two receptor tyrosine kinase-specific inhibitors, amuvatinib and imatinib, for their potential antiviral efficacies against SARS-CoV-2. Amuvatinib blocks SARS-CoV-2 infection by inhibiting ACE2 cleavage and the subsequent soluble ACE2 receptor. All these data suggest that amuvatinib may be a potential therapeutic agent in SARS-CoV-2 prevention for those experiencing vaccine breakthroughs."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases

Development and validation of a cuproptosis-related lncRNA model correlated to the cancer-associated fibroblasts enable the prediction prognosis of patients with osteosarcoma. (PubMed, J Bone Oncol) - "Additionally, we obtained three potentially effective drugs for OS: erlotinib, MP470, and WH-4-023 targeting the PI3K-Akt pathway. The expression level of ZNF37BP was significantly elevated in OS cell lines than in normal osteoblast hFOB1.19 cells, and that of ATP7A, LIPT1, AL353759.1, and AC005034.5 were decreased considerably in OS cell lines. Cuproptosis-related lncRNAs are correlated with the CAFs of osteosarcoma, and this could serve as a foundation for OS survival prediction and treatment."

Journal • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor • ATP7A • CAFs • CD4 • LIPT1

Meta-Data Analysis to Explore the Hub of the Hub-Genes That Influence SARS-CoV-2 Infections Highlighting Their Pathogenetic Processes and Drugs Repurposing. (PubMed, Vaccines (Basel)) - "Then we detected hHub-DEGs guided top-ranked nine candidate drug agents (Digoxin, Avermectin, Simeprevir, Nelfinavir Mesylate, Proscillaridin, Linifanib, Withaferin, Amuvatinib, Atazanavir) by molecular docking and cross-validation for treatment of SARS-CoV-2 infections. Therefore, the findings of this study could be useful in formulating a common treatment plan against SARS-CoV-2 infections globally."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • AKT1 • CXCL8 • EGFR • IL6 • MAPK1 • STAT3 • TP53 • UBA52

βIII-tubulin suppression enhances the activity of Amuvatinib to inhibit cell proliferation in c-Met positive non-small cell lung cancer cells. (PubMed, Cancer Med) - "We also show that this compound significantly inhibits cell proliferation among βIII-tubulin knockdown cells expressing the receptor tyrosine kinase c-Met. Together, our results highlight that βIII-tubulin suppression combined with targeting specific receptor tyrosine kinases may represent a novel therapeutic approach for otherwise difficult-to-treat lung carcinomas."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MET

Late p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes. (PubMed, Sci Rep) - "Moreover, an increased apoptotic rate was observed when the GBM-derived U87MG cells were co-treated with LPS and Temozolomide (TMZ) in comparison to TMZ alone. Moreover, the combined treatment with the RAD51 inhibitor, Amuvatinib in combination with, TMZ after LPS stimulation reduced tumor cell viability more than with each treatment alone. In conclusion, our results suggest that stimulation of TLR4 combined with pharmacological inhibition of the DNA repair pathway may be an alternative treatment for GBM patients."

IO biomarker • Journal • Astrocytoma • Glioblastoma • Oncology • Solid Tumor • RAD51 • TLR4

[VIRTUAL] Targeting DNA Repair to Overcome Drug Resistance in Hodgkin Lymphoma (ASH 2020) - "This neoplasm is curable in the majority of cases with chemotherapy including ABVD (Doxorubicin, Bleomycin, Vinblastine, Dacarbazine) or BEACOPP (Bleomycin, etoposide, Doxorubicin, cyclophosphamide, Vincristine, procarbazine and Prednisone) and/or radiation...We characterized the drug-response of 4 cHL cell lines to DNA repair inhibitors including PJ34 (PARP inhibitor), NU7441 (DNAPK inhibitor), KU55933 (ATM inhibitor), PF477736 (CHK1 inhibitor), AZD6738 (ATR inhibitor), AZD1775 (Wee1 inhibitor), MP-470 (Rad51 inhibitor) and genotoxic agents used in standard chemotherapy (cyclophosphamide, doxorubicin and etoposide)...Alternative treatment options for the subsets of patients for whom first- or second-line therapies fail are needed. These results open new perspectives to improve the treatment of relasped/refractory cHL patients and provide new strategies to overcome drug resistance."

Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Oncology • Transplantation • RAD51

The Amuvatinib Derivative, N-(2H-1,3-Benzodioxol-5-yl)-4-{thieno[3,2-d]pyrimidin-4-yl}piperazine-1-carboxamide, Inhibits Mitochondria and Kills Tumor Cells under Glucose Starvation. (PubMed, Int J Mol Sci) - "In line with the known dependence of glucose-starved cells on the mitochondria, compound 6 inhibits mitochondrial membrane potential. These findings support the concept that tumor cells are dependent on mitochondria under glucose starvation, and bring forth compound 6 as a new molecule with potential antitumor activity for the treatment of glucose-starved tumors."

Journal • Oncology • Solid Tumor

Expression of AXL enhances docetaxel-resistance of prostate cancer cells (PubMed, Zhonghua Nan Ke Xue) - "The elevated expression of AXL enhances the docetaxel-resistance of PC-3 and DU145 prostate cancer cells and AXL intervention improves their chemosensitivity to docetaxel, which may be associated with the increased cell apoptosis in the G2/M phase and decreased expression of ABCB1."

Journal • Biosimilar • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Genome-enabled phylogenetic and functional reconstruction of an araphid pennate diatom Plagiostriata sp. CCMP470, previously assigned as a radial centric diatom, and its bacterial commensal. (PubMed, Sci Rep) - "Notably, our DNA library contains the genome of a bacterium within the Rhodobacterales, an alpha-proteobacterial lineage known frequently to associate with algae. We demonstrate the presence of commensal alpha-proteobacterial sequences in other published algal genome and transcriptome datasets, which may indicate widespread and persistent co-occurrence."

Journal

Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST). (PubMed) - "Targeting c-Kit plus HER1 or AXL/c-Met abrogates IM resistance in GIST."

Journal • Biosimilar • Immunology • Oncology • Sarcoma

SuperGen Inc.: SuperGen 3Q10 financial results (Rodman and Renshaw) -

Analysts expect to see updated results from the P1 program for MP470 in 2011;

Financial analyst • Oncology

Stifel Nicolaus Healthcare Conference (Astex) - Anticipated data from P2 proof-of-concept ESCAPE trial in SCLC in Q4 2012

Anticipated P2 data • Oncology

SuperGen reports 2011 first quarter financial results (Business Wire) -

SuperGen to initiate ESCAPE P2 trial of amuvatinib in SCLC in this quarter;

Anticipated P2 trial initiation • Oncology

A phase 2 study of amuvatinib (MP-470), the first RAD51 inhibitor in combination with platinum-etoposide (PE) in refractory or relapsed small cell lung cancer (ESCAPE) (AACR 2013) - Abstract#: 2095; Presentation Time: Monday, Apr 08, 2013, 1:00 PM - 5:00 PM; P2, N=23; ESCAPE; "Per RECIST 1.1, 2 PRs and 3 SDs were confirmed by follow-up scan ≥ 4 weeks apart for an overall clinical benefit rate (CBR) of 5/23 (22%). No CRs were observed. Grade 3/4 suspected amuvatinib related AEs were neutropenia, thrombocytopenia, atrial fibrillation, diarrhea, esophagitis, and hypercalcemia (1 patient each; 4%); hypokalemia and leukopenia, (2 patients each; 9%)."

P2 data • Oncology

A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors (Cancer Chemother Pharmacol) - P1, N=22; NCT00894894; PMID: 23178951; "No dose-limiting toxicities were reported with amuvatinib DPC up to 1,500 mg/day, given as one or in divided doses, for 1-6 cycles. No maximum tolerated dose was reached. Five patients had serious adverse events, all unrelated to treatment. Exposure levels were low and variable."

P1 data • Oncology

Amuvatinib (MP-470), an oral dual inhibitor of mutant kinases and DNA repair: Final results from a 100-patient, 5-arm phase Ib trial in combination with five standard of care (SOC) anticancer regimens (ASCO 2011) - Presentation time: Mon, Jun 6, 8:00 AM - 12:00 PM; SGI-0470-02; P1, N=102; Enrolled=100; Amuvatinib did not alter the PK of SOC agents, except docetaxel; MTD was not reached & amuvatinib-related DLTs were not identified in this study; 12 PRs and 44 SDs by RECIST criteria were observed for an overall DCR of 56%; PC & CE combination arms with amuvatinib showed the most activity with 6 & 5 PRs, respectively;

Oncology

Doxorubicin as a fluorescent reporter identifies novel MRP1 (ABCC1) inhibitors missed by calcein-based high content screening of anticancer agents. (PubMed, Biomed Pharmacother) - "Six drugs (afatinib, celecoxib, doramapimod, mifepristone, MK-2206 and rosiglitazone) were evaluated for their ability to reverse resistance of MRP1-overexpressing H69AR lung cancer cells against vincristine, doxorubicin and etoposide...Anti-cancer agents that exhibit MRP1 inhibition may be used to reverse multidrug resistance or to improve the efficacy and reduce the toxicity of various cancer chemotherapies. On the other hand, anti-cancer drugs that did not interact with MRP1 carry a low risk for developing MRP1-mediated resistance."

Journal

Design, synthesis, biological evaluation and molecular modeling study of new thieno[2,3-d]pyrimidines with anti-proliferative activity on pancreatic cancer cell lines. (PubMed, Bioorg Chem) - "In this study, twenty eight new compounds based on thieno[2,3-d]pyrimidine scaffold were synthesized as anti-pancreatic cancer agents mimicking the benzofuro[3,2-d]pyrimidine derivative, amuvatinib...Docking study was carried out into PDGFR-α active site which showed comparable binding mode to that of FDA approved PDGFR-α inhibitor, imatinib. 3D-Quantitative structure activity relationship (QSAR) model was built up with five-featured pharmacophore which could be implemented for emerging effective lead structures. These compounds could serve as a new chemotype for discovering new agents for pancreatic cancer therapy."

Journal • Preclinical