Drug- Drug Interaction Study of JI-101 & Everolimus in Advanced Solid Tumors, Expansion Pharmacodynamic Study of JI-101 in Advanced Low Grade Endocrine Tumors, Ovarian Cancers or K-RAS Mutant Colon Cancers

The study consists of two parts: Drug Interaction (Pharmacokinetic) Phase and Pharmacodynamic Phase
The primary study objective for the Drug Interaction Study is to determine the pharmacokinetic interactions between RAD001 and JI-101.
The primary study objective for the Pharmacodynamic Study is progression-free survival at 2 moths, evaluated separately in each of the three cohorts.
These will include a determination of tumor response using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria and an assessment of ephrinB4 expression in blood samples.
Secondary objectives are to determine safety and tolerability of JI-101. The investigational products are everolimus (42-O-(2-hydroxyethyl) rapamycin) and JI-101 (1-[1-(2-amino-pyridin-4-ylmethyl)-1H-indol-4-yl]-3-(5-bromo-2 methoxy-phenyl)-urea)
Eligible patients meeting all study entry criteria will be enrolled in the study. For the Drug Interaction study, patients with solid tumors will receive a single dose (10 mg) of Everolimus by mouth on Day 1 and Day 8 and JI-101 capsules (200 mg) by mouth on Day 8 and Day 15. For the Pharmacodynamic Study, all patients will receive JI-101 capsules by mouth (200 mg BID) for 28 day treatment cycles.

Start Date01 Sep 2010

Sponsor / Collaborator

University of Utah

[+1]

NCT00842335

/ CompletedPhase 1/2

A Multicenter, Phase 1/2, Open-Label, Dose-Escalation Study of JI-101, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors

The purpose of this study, the first clinical trial of JI-101, is to determine the maximum tolerated dose of JI-101 when given orally to patients with solid tumors. Safety, tolerability, pharmacokinetics, pharmacodynamics, and the effects of the drug on tumor metabolism will also be studied. JI-101 is an inhibitor of new blood vessel growth that may provide benefit to patients with solid tumors that have failed standard therapeutic regimens.

Start Date01 Feb 2009

Sponsor / Collaborator

Jubilant Innovation Pte Ltd.

100 Clinical Results associated with VEGFR2 x EphB4

100 Translational Medicine associated with VEGFR2 x EphB4

0 Patents (Medical) associated with VEGFR2 x EphB4

Literatures (Medical) associated with VEGFR2 x EphB4

15 Apr 2025·ACS Omega

Discovery of Novel Multiangiogenic Agents Targeting VEGFR2, EphB4, FGFR-1, and TIE-2: Receptor-Based Pharmacophore Modeling, Virtual Screening, and Molecular Modeling Studies

Article

Author: Patra, Jeevan ; Keshari, Amit K. ; Bhandare, Richie R. ; Parrot, Madison ; Lin, Shiru ; Shaik, Afzal B.

The angiogenesis phenomenon is crucial for the formation of new blood vessels in cancer cells. The cancerous cells' progress hampers other healthy cells. The main objective of this study is to explore and decipher multimodal natural compounds against VEGFR2, EphB4, FGFR-1, and TIE-2 drug targets to arrest angiogenesis and progression. The receptor-based pharmacophore modeling of VEGFR2, EphB4, FGFR-1, and TIE-2 was developed and validated through enrichment parameters. Further, the validated hypothesis allowed for screening druglike natural product databases such as SuperNatural 3.0, COCONUT, and LOTUS. The common pharmacophoric featured natural compounds were assessed for binding affinities using absolute end-point methods. Finally, density functional theory has been studied to understand the chemical reactivity and stability of the protein complexes. Among all of the screened natural compounds, 17 natural compounds were found to align accurately against validated pharmacophore models having higher fitness scores and align scores. Taking reference drugs sorafenib (VEGFR2), NVP-BHG712 (EphB4), pemiganitib (FGFR-1), and DP1919 (TIE-2), three promising natural compounds CNP0003920, CNP0243075, and CNP0211397 were concluded based on their end-point binding energies, binding interactions, molecular dynamics, and optimal pharmacokinetic and toxicity profiles. The density functional theory (DFT) results suggested that the identified compounds bound with protein complexes are stable. Our findings can represent a promising starting point for developing multimodal analogues VEGFR2, EphB4, FGFR-1, and TIE-2 proteins.

01 Aug 2024·Journal of Gastrointestinal Oncology

Proteome-wide Mendelian randomization and single-cell sequencing analysis identify the association between plasma proteins and gastric cancer

Article

Author: Lei, Zilong ; Jin, Yichen ; Li, Peixin ; Lyu, Guoruiyu

BackgroundTargeted therapy is a crucial treatment modality for advanced gastric cancer, with several targets already identified, and the exploration of new targets is important. In this study, our aim was to identify plasma proteins causally associated with gastric cancer to explore novel genetic targets for the disease.MethodsFirstly, we utilized protein quantitative trait loci data for 4,907 plasma proteins and genome-wide association study data for gastric cancer to conduct Mendelian randomization (MR) analyses. This was followed by summary-data-based MR analysis on the identified plasma proteins. We then analyzed single-cell sequencing data from the Gene Expression Omnibus database to describe the distribution of genes corresponding to these proteins across different stages and cell types of gastric cancer.ResultsMR analysis identified 12 plasma proteins with potential causal associations with gastric cancer, among which motilin (MLN) and THSD1 passed the summary-data-based MR test. These proteins showed no evidence of pleiotropy nor heterogeneity. In single-cell sequencing analysis, EPHB4, KDR, SEMA6B, CDH1, and C1GALT1C1 were found to be enriched in specific cell types within gastric cancer. KDR and LIFR exhibited significant differential expression between gastric cancer and normal tissues. All the 12 genes displayed differential expression across different stages of gastric cancer.ConclusionsOverall, our study identified several plasma proteins with potential causal relationships to gastric cancer. This provides potential candidate targets for gastric cancer research and advances our understanding of the disease's genetic foundations.

01 Apr 2024·Bioorganic Chemistry

Novel multi-target angiogenesis inhibitors as potential anticancer agents: Design, synthesis and preliminary activity evaluation

Article

Author: Qu, Jingkun ; Zhang, Qingqing ; Zhang, Jie ; Zhang, Junyu ; Li, Zilong ; Pan, Xiaoyan ; Li, Yanchen

Based on the crucial role of histone deacetylase (HDAC) and receptor tyrosine kinase in angiogenesis, in situ assembly, skeletal transition, molecular hybridization, and pharmacophore fusion were employed to yield seventy-six multi-target angiogenesis inhibitors. Biological evaluation indicated that most of the compounds exhibited potent proliferation inhibitory activity on MCF-7 cells, with the TH series having the highest inhibitory activity on MCF-7 cells. In addition, the IC₅₀ values of TA11 and TH3 against HT-29 cellswere 0.078 μmol/L and 0.068 μmol/L, respectively. The cytotoxicity evaluation indicated that TC9, TA11, TM4, and TH3 displayed good safety against HEK293T cells. TH2 and TH3 could induce apoptosis of MCF-7 cells. Molecular modeling and ADMET prediction results indicated that most of target compounds showed promising medicinal properties, which was consistent with the experimental results. Our findings provided new lead compounds for the structural optimization of multi-target angiogenesis inhibitors.

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