Evidence map›Paper›PMID 41488912›Full record

ArticleRSC chemical biology2026

An AKR1C3-activated kinase inhibitor prodrug.

Zhengnian Li, Michael Martinez, Woong Sub Byun, Anuradha Thathireddy, Tian Qiu, Yaning Wang, Leon Katzengruber, Ani Chouldjian, Wenchao Lu, Wenzhi Ji and 4 more

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In one paragraph

Article in RSC chemical biology, 2026. 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
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.

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

14 authors.

Zhengnian LiDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University Stanford CA USA nsgray01@stanford.edu hinshaw@stanford.edu.
Michael MartinezDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University Stanford CA USA nsgray01@stanford.edu hinshaw@stanford.edu.
Woong Sub ByunDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University Stanford CA USA nsgray01@stanford.edu hinshaw@stanford.edu.
Anuradha ThathireddyDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University Stanford CA USA nsgray01@stanford.edu hinshaw@stanford.edu.
Tian QiuDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University Stanford CA USA nsgray01@stanford.edu hinshaw@stanford.edu.ORCID https://orcid.org/0000-0002-7168-0715
Yaning WangDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University Stanford CA USA nsgray01@stanford.edu hinshaw@stanford.edu.
Leon KatzengruberDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University Stanford CA USA nsgray01@stanford.edu hinshaw@stanford.edu.ORCID https://orcid.org/0009-0001-9677-6975
Ani ChouldjianDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University Stanford CA USA nsgray01@stanford.edu hinshaw@stanford.edu.
Wenchao LuDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University Stanford CA USA nsgray01@stanford.edu hinshaw@stanford.edu.ORCID https://orcid.org/0000-0003-1175-365X
Wenzhi JiDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University Stanford CA USA nsgray01@stanford.edu hinshaw@stanford.edu.
Jianwei CheDepartment of Cancer Biology, Dana-Farber Cancer Institute Boston Massachusetts USA.
Tinghu ZhangDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University Stanford CA USA nsgray01@stanford.edu hinshaw@stanford.edu.
Stephen M HinshawDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University Stanford CA USA nsgray01@stanford.edu hinshaw@stanford.edu.ORCID https://orcid.org/0000-0003-4215-5206
Nathanael S GrayDepartment of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University Stanford CA USA nsgray01@stanford.edu hinshaw@stanford.edu.

Funding

Degrading therapeutically important kinases using small moleculesR01CA218278 · NCI · STANFORD UNIVERSITY · PI Eric Sebastian Fischer, NATHANAEL Schiander GRAY · 2019 to 2026
$4.6M
NCI NIH HHS R01 CA218278
6 · The paper itself

Abstract

Enzymatically activated prodrugs can enable context-specific target inhibition. AKR1C3 is an NADPH-dependent aldo-ketoreductase involved in androgen metabolism, prostaglandin synthesis, and cell proliferation that is overexpressed in tumors, making it an ideal candidate for tumor-specific prodrug activation. Reported prodrugs that exploit AKR1C3 catalytic activity release DNA-intercalating toxins or other non-selective poisons upon enzymatic activation. OBI-3424, a prodrug of a DNA alkylating agent, is a prominent example of this strategy. To extend this concept to selective enzymatic inhibitors, we have developed AKR1C3-activated prodrugs of OTS964, a CDK11 inhibitor. We have probed the activities of the compounds with biochemical and cellular assays, finding specific activation of the lead prodrug by AKR1C3. Upon enzymatic conversion, the compound recapitulates the cellular activity of the parent compound. These results demonstrate that the AKR1C3-activated prodrug strategy can be used to convert selective kinase inhibitors into context-dependent prodrugs. Extension of this approach may enable synthesis of prodrugs for targeted therapies that spare normal tissue, further improving their therapeutic windows.

Identifiers

PMID41488912
PMCPMC12757751

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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.