Evidence map›Paper›PMID 29118584›Full record

ArticleOncoTargets and therapy2017

Developing a novel dual PI3K-mTOR inhibitor from the prodrug of a metabolite.

Yan Zhou, Genyan Zhang, Feng Wang, Jin Wang, Yanwei Ding, Xinyu Li, Chongtie Shi, Jiakui Li, Chengkon Shih, Song You

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in OncoTargets and therapy, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact, top 88% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed, 1 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 2 institutions in 1 country.

Yan ZhouThe School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, Shenyang.
Genyan ZhangDepartment of Project Management, Medicinal Chemistry, Pharmacology, Drug Metabolism, and Pharmacokinetics, Toxicology, Xuanzhu Pharma, Jinan, China.
Feng WangDepartment of Project Management, Medicinal Chemistry, Pharmacology, Drug Metabolism, and Pharmacokinetics, Toxicology, Xuanzhu Pharma, Jinan, China.
Jin WangDepartment of Project Management, Medicinal Chemistry, Pharmacology, Drug Metabolism, and Pharmacokinetics, Toxicology, Xuanzhu Pharma, Jinan, China.
Yanwei DingDepartment of Project Management, Medicinal Chemistry, Pharmacology, Drug Metabolism, and Pharmacokinetics, Toxicology, Xuanzhu Pharma, Jinan, China.
Xinyu LiDepartment of Project Management, Medicinal Chemistry, Pharmacology, Drug Metabolism, and Pharmacokinetics, Toxicology, Xuanzhu Pharma, Jinan, China.
Chongtie ShiDepartment of Project Management, Medicinal Chemistry, Pharmacology, Drug Metabolism, and Pharmacokinetics, Toxicology, Xuanzhu Pharma, Jinan, China.
Jiakui LiDepartment of Project Management, Medicinal Chemistry, Pharmacology, Drug Metabolism, and Pharmacokinetics, Toxicology, Xuanzhu Pharma, Jinan, China.
Chengkon ShihDepartment of Project Management, Medicinal Chemistry, Pharmacology, Drug Metabolism, and Pharmacokinetics, Toxicology, Xuanzhu Pharma, Jinan, China.
Song YouThe School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, Shenyang.
PharmacoGenetics (China) · CNShenyang Pharmaceutical University · CN

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

This study presents a process of developing a novel PI3K-mTOR inhibitor through the prodrug of a metabolite. The lead compound (compound 1) was identified with similar efficacy as that of NVP-BEZ235 in a tumor xenograft model, but the exposure of compound 1 was much lower than that of NVP-BEZ235. After reanalysis of the blood sample, a major metabolite (compound 2) was identified. Compound 2 exerted similar in vitro activity as compound 1, which indicated that compound 2 was an active metabolite and that the in vivo efficacy in the animal model came from compound 2 instead of compound 1. However, compound 1 was metabolized into compound 2 predominantly in the liver microsomes of mouse, but not in the liver microsomes of rat, dog, or human. In order to translate the efficacy in the animal model into clinical development or predict the pharmacokinetic/pharmacodynamic parameters in the clinical study using a preclinical model, we developed the metabolite (compound 2) instead of compound 1. Due to the low bioavailability of compound 2, its prodrug (compound 3) was designed and synthesized to improve the solubility. The prodrug was quickly converted to compound 2 through both intravenous and oral administrations. Because the prodrug (compound 3) did not improve the oral exposure of compound 2, developing compound 3 as an intravenous drug was considered by our team, and the latest results will be reported in the future.

Indexed as

antitumormetabolitemTORNVP-BEZ235PI3Kprodrug

Identifiers

PMID29118584
PMCPMC5659256
OpenAlexW2765182545

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.