Evidence map›Paper›PMID 38858089›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2024

Preclinical Systemic Pharmacokinetics, Dose Proportionality, and Central Nervous System Distribution of the ATM Inhibitor WSD0628, a Novel Radiosensitizer for the Treatment of Brain Tumors.

Sneha Rathi, Ju-Hee Oh, Wenjuan Zhang, Ann C Mladek, Darwin A Garcia, Zhiyi Xue, Danielle M Burgenske, Wenqiu Zhang, Jiayan Le, Wei Zhong and 2 more

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In one paragraph

Article in The Journal of pharmacology and experimental therapeutics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
–field-weighted citation impact
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

8 citing papers in PubMed.

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

12 authors.

Sneha RathiBrain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.) elmq011@umn.edu rathi029@umn.edu.ORCID 0000-0002-4631-0085
Ju-Hee OhBrain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.).
Wenjuan ZhangBrain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.).
Ann C MladekBrain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.).
Darwin A GarciaBrain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.).
Zhiyi XueBrain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.).
Danielle M BurgenskeBrain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.).
Wenqiu ZhangBrain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.).
Jiayan LeBrain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.).
Wei ZhongBrain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.).
Jann N SarkariaBrain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.).
William F ElmquistBrain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.) elmq011@umn.edu rathi029@umn.edu.

Funding

Therapy Evaluation CoreU19CA264362 · NCI · MAYO CLINIC ROCHESTER · PI PARNEY, IAN F · 2021 to 2025
$7.6M
Pre-Clinical Novel Radiosensitizer Evaluation Program for Brain TumorsU01CA227954 · NCI · MAYO CLINIC ROCHESTER · PI SARKARIA, JANN N. · 2018 to 2022
$3.0M
NCI NIH HHS U01 CA227954NCI NIH HHS U19 CA264362
6 · The paper itself

Abstract

Radiation therapy, a standard treatment option for many cancer patients, induces DNA double-strand breaks (DSBs), leading to cell death. Ataxia telangiectasia mutated (ATM) kinase is a key regulator of DSB repair, and ATM inhibitors are being explored as radiosensitizers for various tumors, including primary and metastatic brain tumors. Efficacy of radiosensitizers for brain tumors may be influenced by a lack of effective drug delivery across the blood-brain barrier. The objective of this study was to evaluate the systemic pharmacokinetics and mechanisms that influence the central nervous system (CNS) distribution of WSD0628, a novel and potent ATM inhibitor, in the mouse. Further, we have used these observations to form the basis of predicting effective exposures for clinical application. We observed a greater than dose proportional increase in exposure, likely due to saturation of clearance processes. Our results show that WSD0628 is orally bioavailable and CNS penetrant, with unbound partitioning in CNS (i.e., unbound tissue partition coefficient) between 0.15 and 0.3. CNS distribution is not limited by the efflux transporters P-glycoprotein and breast cancer resistant protein. WSD0628 is distributed uniformly among different brain regions. Thus, WSD0628 has favorable pharmacokinetic properties and potential for further exploration to determine the pharmacodynamics-pharmacokinetics efficacy relationship in CNS tumors. This approach will provide critical insights for the clinical translation of WSD0628 for the treatment of primary and secondary brain tumors. SIGNIFICANCE STATEMENT: This study evaluates the preclinical systemic pharmacokinetics, dose proportionality, and mechanisms influencing CNS distribution of WSD0628, a novel ATM inhibitor for the treatment of brain tumors. Results indicate that WSD0628 is orally bioavailable and CNS penetrant without efflux transporter liability. We also observed a greater than dose proportional increase in exposure in both the plasma and brain. These favorable pharmacokinetic properties indicate WSD0628 has potential for further exploration for use as a radiosensitizer in the treatment of brain tumors.

Indexed as

Ataxia Telangiectasia Mutated ProteinsBrain NeoplasmsRadiation-Sensitizing AgentsAnimalsATP Binding Cassette Transporter, Subfamily B, Member 1ATP Binding Cassette Transporter, Subfamily G, Member 2Central Nervous SystemDose-Response Relationship, DrugFemaleMaleMiceTissue DistributionAbcg2 protein, mouseAtaxia Telangiectasia Mutated ProteinsATP Binding Cassette Transporter, Subfamily B, Member 1ATP Binding Cassette Transporter, Subfamily G, Member 2Radiation-Sensitizing Agents

Identifiers

PMID38858089
PMCPMC11264258

What OpenQuestion holds

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Registered trials

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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.