golvatinib (E7050) / Eisai - LARVOL DELTA

Influence of Retrogression and Re-Aging Parameters on the Microstructure and Hardness of Jet-Formed 7050 Alloy. (PubMed, Materials (Basel)) - "In this paper, regression and re-aging treatment (RRA) was performed on the 7050 alloy, and the evolution in the microstructure of the 7050 alloy was observed by metallography and SEM...Meanwhile, the precipitates on the grain boundaries gradually increased in size, while the number of precipitates within the grain boundaries correspondingly decreased. These results reveal the influence of the re-aging treatment on the microstructure and mechanical properties of 7050 aluminum alloy, providing an important experimental basis for further optimizing the performance of the alloy."

Journal

Preparation and antibacterial properties of benzisothiazolinone quaternized chitosan derivatives for sustainable fuel preservation. (PubMed, Carbohydr Polym) - "Furthermore, HACCBIT also inhibited the corrosion of the 7050‑aluminum alloy used in fuel tanks for >84 h. This study demonstrated that covalently linking BIT to chitosan via electronic splicing techniques, effectively mitigates the deficiencies of BIT while demonstrating a unique bactericidal action against bacteria in aviation fuel. It also safeguards metal components within fuel tanks, thereby enhancing the potential of polysaccharide derivatives as effective antibacterial agents in fuel systems."

Journal • Infectious Disease

Quantification and analyses of seven tyrosine kinase inhibitors targeting hepatocellular carcinoma in human plasma by QuEChERS and UPLC-MS/MS. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "Herein, seven TKIs, namely sorafenib tosylate, axitinib, erlotinib, cediranib, brivanib, linifanib, and golvatinib, were successfully analyzed in human plasma by following a quick, easy, cheap, effective, rugged, and safe (QuEChERS) pretreatment method combined with ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)...In this study, dovitinib was used as the internal standard...The intraday and interday accuracy values ranged from -6.12 % to 7.31 %, with a precision (RSD) of ≤ 10.57 %. The method was rapid, accurate, specific, simple, reproducible, and suitable for the quantitative determination of the seven TKIs in human plasma."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

E7050 Suppresses the Growth of Multidrug-Resistant Human Uterine Sarcoma by Inhibiting Angiogenesis via Targeting of VEGFR2-Mediated Signaling Pathways. (PubMed, Int J Mol Sci) - "E7050 treatment also decreased the expression of CD31 and p-VEGFR2 in MES-SA/Dx5 tumor tissue sections in comparison with the vehicle control. Collectively, E7050 may serve as a potential agent for the treatment of cancer and angiogenesis-related disorders."

Journal • Oncology • Sarcoma • Solid Tumor • CD31 • PECAM1

The antiviral activity of a small molecule drug targeting the NSP1-ribosome complex against Omicron, especially in elderly patients. (PubMed, Front Cell Infect Microbiol) - "Golvatinib, Gliquidone, and Dihydroergotamine were superior to other compounds in the crystal structure of binding conformation and free energy. In particular, Golwatinib provides a candidate for treatment and prophylaxis in elderly patients with Omicjon, suggesting further evaluation of the anti-SARS-CoV-2 activity of these compounds in cell culture. Further studies are needed to determine the utility of this finding through prospective clinical trials and identify other meaningful drug combinations."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Blockade of c-Met-Mediated Signaling Pathways by E7050 Suppresses Growth and Promotes Apoptosis in Multidrug-Resistant Human Uterine Sarcoma Cells. (PubMed, Int J Mol Sci) - "E7050 treatment also decreased the expression of Ki-67 and p-Met, and increased the expression of cleaved caspase-3 in MES-SA/Dx5 tumor sections. Therefore, E7050 is a promising drug that can be developed for the treatment of multidrug-resistant uterine sarcoma."

Journal • Oncology • Sarcoma • Solid Tumor • BAX • BIRC5 • CASP3 • CCNA2 • CCND1 • CDKN1A • MET

Umpolung Synthesis of Pyridyl Ethers by Bi(V)-Mediated O-Arylation of Pyridones. (PubMed, Angew Chem Int Ed Engl) - "The utility of this umpolung approach to pyridyl ethers, which is complementary to conventional methods based on S N Ar or cross-coupling, is demonstrated through the concise synthesis of Ki6783 and picolinafen, and the formal synthesis of cabozantib and golvatinib. Computational investigations reveal that arylation proceeds in a concerted fashion via a 5-membered transition state. The kinetically-controlled regioselectivity for O-arylation - which is reversed relative to previous Bi(V)-mediated pyridone arylations - is attributed primarily to the geometric constraints imposed by the bismacyclic scaffold."

Journal

Microstructural Evolution and Hardness Responses of 7050 Al Alloy during Processing. (PubMed, Materials (Basel)) - "Moreover, the variation of recrystallization before and after heat treatment was strongly dependent on the cooling path after deformation. Finally, this study provided a general understanding on the relationship between microstructural evolution and harness of the 7050 alloy."

Journal

In silico screening of c-Met tyrosine kinase inhibitors targeting nucleotide and drug-substrate binding sites of ABCB1 as potential MDR reversal agents. (PubMed, J Recept Signal Transduct Res) - "Additionally, as a potential repositioning drug, MD simulation studies of golvatinib, corroborated the docking results. We applied docking and molecular dynamics simulations to screen the potential c-Met inhibitors as the MDR reversing agents targeting ATP and drug-substrate binding sites, and the results suggested several repurposed candidate drugs."

Journal • Oncology • ABCB1 • MET

Effect of Grain Refiner on Fracture Toughness of 7050 Ingot and Plate. (PubMed, Materials (Basel)) - "The fracture toughness of the 7050-T7651 plate produced using the Al-3Ti-0.15C ingot was approximately 2-6 MPa · m higher than the plate produced from the Al-5Ti-0.2B ingot. Fractography of the failed fracture toughness specimens revealed that the path of crack propagation of the 7050 ingot after heat treatment produced from the Al-3Ti-0.15C grain refiner was more tortuous than in the ingot produced from the Al-5Ti-0.2B, which resulted in higher fracture toughness."

Journal • Musculoskeletal Diseases • Orthopedics

A Study of E7050 in Combination With E7080 in Participants With Advanced Solid Tumors (Dose Escalation) and in Participants With Recurrent Glioblastoma or Unresectable Stage III or Stage IV Melanoma After Prior Systemic Therapy (Expansion Cohort and Phase 2) (clinicaltrials.gov) - P1b/2; N=30; Terminated; Sponsor: Eisai Inc.; Completed ➔ Terminated; Study was terminated by the sponsor early at the end of Phase 1b due to a change in corporate strategy.

Clinical • Combination therapy • Trial termination • Brain Cancer • Glioblastoma • Melanoma • Neutropenia • Oncology • Solid Tumor

Incidence and comorbidities of disruptive behavior disorders diagnosed in Finnish specialist psychiatric services. (PubMed, Soc Psychiatry Psychiatr Epidemiol) - "Although DBDs were 3.5 times more common among boys during the whole follow-up period, the yearly incidence during adolescence was fairly similar between boys and girls. DBD existed alongside various psychiatric disorders at a relatively young age and only a minor increase in treated incidence was found during childhood."

Journal • Behavior Disorders • CNS Disorders • Mental Retardation • Psychiatry

Design, synthesis and biological evaluation of novel 4-(pyrrolo[2,3-d]pyrimidine-4-yloxy)benzamide derivatives as potential antitumor agents. (PubMed, Bioorg Med Chem Lett) - "Among them, the optimal compound 35 was found to possess excellent inhibitory activity against the A549, Hela and MCF-7 cell lines with IC values of 5.29 ± 0.58, 3.72 ± 0.91, and 9.23 ± 0.56 μM, which were superior to Golvatinib. The structure-activity relationship showed that the introduction of 7H-pyrrolo[2,3-d]pyrimidine along with the F atom of the central and terminal benzene was beneficial to the improvement of inhibitory activity of the target compounds. Besides, we took further study on the combined mode between compound 35 and c-Met kinase through molecular docking."

Journal • Oncology • MET

Diverse Receptor Tyrosine Kinase Phosphorylation in Urine-Derived Tubular Epithelial Cells from Autosomal Dominant Polycystic Kidney Disease Patients. (PubMed, Nephron) - "Analysis of urine-derived tubular epithelial cells demonstrated diverse RTK phosphorylation in ADPKD, and Met phosphorylation was noted in some patients. Considering the difference in the effects of golvatinib on immortalized tubular epithelial cells among patients, this analysis may aid in selecting suitable drugs for individual ADPKD patients."

Clinical • Journal • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • SLC2A3

E7050 in combination with E7080 in subjects with advanced solid tumors (Dose escalation) and in subjects with recurrent glioblastoma or unresectable stage III or stage IV melanoma after prior systemic therapy (Expansion cohort and phase 2) (clinicaltrials.gov) - P1/2, N=226; Not yet recruiting -> Recruiting

Enrollment open • Melanoma • Oncology

E7050 in Combination With Sorafenib Versus Sorafenib Alone as First Line Therapy in Patients With Hepatocellular Carcinoma (clinicaltrials.gov) - P1/2; N=95; Active, not recruiting; Sponsor: Eisai Inc.; Recruiting -> Active, not recruiting

Enrollment closed • Biosimilar • Hepatocellular Cancer • Oncology

Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR mutant lung cancer (Mol Cancer Ther) - PC-9/HGF cells with an exon 19 deletion, H1975 with an L858R mutation & HCC827ER with an exon 19 deletion, with acquired resistance to erlotinib due to HGF gene transfection, gatekeeper T790M mutation & Met amplification, respectively; WZ4002 inhibited the growth of H1975 cells with a gatekeeper T790M mutation, but did not inhibit the growth of HCC827ER & PC-9/HGF cells; HGF triggered the resistance of H1975 cells to WZ4002, whereas E7050 sensitized HCC827ER, PC-9/HGF, & HGF-treated H1975 cells to WZ4002, inhibiting EGFR & Met phosphorylation & their downstream molecules; Combined treatment potently inhibited the growth of tumors induced in SCID mice by H1975, HCC827ER & PC-9/HGF cells, without any marked adverse events

Preclinical • Oncology

Design, Synthesis, and Biological Evaluation of Pyridineamide Derivatives Containing a 1,2,3-Triazole Fragment as Type II c-Met Inhibitors. (PubMed, Molecules) - "Among them, the promising compound B26 showed stronger inhibitory activity than Golvatinib, with IC values of 3.22, 4.33, and 5.82 μM against A549, HeLa, and MCF-7 cell lines, respectively...Meanwhile, the optimal compound B26 showed potent biological activity in some pharmacological experiments in vitro, such as cell morphology study, dose-dependent test, kinase activity assay, and cell cycle experiment. Finally, the molecular docking simulation was performed to further explore the binding mode of compound B26 with c-Met."

Journal • Oncology

Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor targeted multi-kinase inhibitor, administered orally QD to patients with advanced solid tumors (ASCO 2012) - Presentation time: Sat, Jun 2, 1:15 PM - 5:15 PM; Anticipated presentation at ASCO 2012

Anticipated data presentation • Oncology

Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor targeted multi-kinase inhibitor, administered orally QD to patients with advanced solid tumors (ASCO 2012) - Presentation time: Saturday Jun 2, 1:15 PM to 5:15 PM; P1, N=34; E7050-E044-101; MTD was 400 mg QD; Best response was SD in 6 pts lasting >84 days; PK showed high variability and plasma concentration increased with dose

P1 data • Oncology

E7050 in combination with cisplatin and capecitabine versus cisplatin and capecitabine alone in patients with advanced or metastatic solid tumors and previously untreated gastric cancer (clinicaltrials.gov) - P1/2, N=7; Sponsor: Eisai; Active, not recruiting -> Terminated (Sites not recruiting).

Trial termination • Oncology

Phase I/II study of E7050 (golvantinib) in combination with sorafenib in patients (pts) with advanced hepatocellular carcinoma (HCC): Phase I results (ASCO-GI 2013) - P1/2, N=13; NCT01271504; "Confirmed partial responses (PRs) were observed in 2/12 (17%) pts and durable SD was observed in 4/13 (31%) pts based on investigator assessment"

P1 data • Oncology

Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor targeted multi-kinase inhibitor, administered orally BID to patients with advanced solid tumors (ASCO 2012) - Presentation time: Mon, Jun 4, 8:00 AM - 12:00 PM; Anticipated presentation at ASCO 2012

Anticipated data presentation • Oncology

Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor targeted multi-kinase inhibitor, administered orally BID to patients with advanced solid tumors (ASCO 2012) - Presentation time: Monday June 4, 8:00 AM to 12:00 PM; P1, N=16; Responses included 4 stable diseases (84-113 days) in 3 pts with gastric cancer and 1 patient with NSCLC, 11 progressive diseases, and 1 non evaluable; The golvatinib plasma concentration after first-dose reached Cmax at a median time of 2 to 4 hours, and declined bi-exponentially with a t½ of approximately 40 hours

P1 data • Oncology

Design, synthesis and biological evaluation of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment. (PubMed, Bioorg Med Chem Lett) - "Among them, the most promising compound 40 showed excellent activity against A549, HeLa and MCF-7 cell lines with IC values of 1.03, 1.15 and 2.59 μM, respectively, which was 2.606.95 times more active than that of Golvatinib. The structure-activity relationships (SARs) showed that the introduction of 5-methylpyridazin-3(2H)-one to "5-atom linker" and the modification of the amide with morpholine group were beneficial for enhancing the inhibitory activity of compounds. In addition, the further research on compound 40 mainly include c-Met kinase activity, concentration dependence, apoptosis (acridine orange staining), and molecular docking."

Journal • MET