Evidence map›Paper›PMID 42623604›Full record

ArticleJournal of medicinal chemistry2026

Selective Macrocyclic WEE1 Kinase Inhibitors with Strong Efficacy against Patient-Derived Colorectal Cancer Organoids.

Joel L Syphers, Josephine A Wright, Adarsh Kumar, Nikos To, Lewis Elson, Andreas Krämer, Susanne Müller, Viktoria Morasch, Aeson Chang, Savannah Young and 15 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of medicinal chemistry, 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

25 authors.

Joel L SyphersMonash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria3052, Australia.ORCID 0009-0001-7139-3863
Josephine A WrightPrecision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia5000, Australia.
Adarsh KumarInstitute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438Frankfurt am Main, Germany.
Nikos ToInstitute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438Frankfurt am Main, Germany.
Lewis ElsonInstitute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438Frankfurt am Main, Germany.
Andreas KrämerInstitute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438Frankfurt am Main, Germany.
Susanne MüllerInstitute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438Frankfurt am Main, Germany.ORCID 0000-0003-2402-4157
Viktoria MoraschInstitute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438Frankfurt am Main, Germany.
Aeson ChangMonash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria3052, Australia.
Savannah YoungMonash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria3052, Australia.
Erica K SloanMonash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria3052, Australia.
Rebekah de NysAdelaide Medical School, Adelaide University, Adelaide, South Australia5000, Australia.
Tharindie N SilvaAdelaide Medical School, Adelaide University, Adelaide, South Australia5000, Australia.ORCID 0000-0003-2852-7704
Laura VrbanacAdelaide Medical School, Adelaide University, Adelaide, South Australia5000, Australia.
Kate R BarrattAdelaide Medical School, Adelaide University, Adelaide, South Australia5000, Australia.
Julia LeeflangAdelaide Medical School, Adelaide University, Adelaide, South Australia5000, Australia.
Sadia T HasanAdelaide Medical School, Adelaide University, Adelaide, South Australia5000, Australia.
Robert W GableSchool of Chemistry, University of Melbourne, Parkville, Victoria3010, Australia.ORCID 0000-0002-4626-0217
Stefan KnappInstitute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438Frankfurt am Main, Germany.ORCID 0000-0001-5995-6494
Daniel L WorthleyPrecision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia5000, Australia.
Siddhartha MukherjeeDepartment of Medicine, Columbia University Medical Center, New YorkNew York10032, United States.
Kieran StocktonMonash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria3052, Australia.
Susan L WoodsPrecision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia5000, Australia.
Daniel L PriebbenowMonash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria3052, Australia.ORCID 0000-0002-7840-0405
Jonathan B BaellMonash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria3052, Australia.ORCID 0000-0003-2114-8242

Funding

Australian Government Research Training Program Scholarship NAFaculty of Health Science at the University of Adelaide NAMonash Graduate Excellence Scholarship provided by Monash University NANational Health and Medical Research Council NASouth Australian Health and Medical Research Institute NAThe Gastroenterological Society of Australia Bushell Research Fellowship NATherapeutic Innovation Australia (TIA), Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program NA
6 · The paper itself

Abstract

Macrocyclization can enhance the selectivity of acyclic compounds toward structurally similar biological targets such as kinases. WEE1 regulates cellular homeostasis and is a promising target in oncology. The clinical candidate AZD1775 (1) failed to progress past Phase II trials because of patient tolerability issues, likely due to off-target inhibition of polo-like kinase 1 (PLK1). Herein, a computer-aided drug design approach was conducted to develop a macrocycle based on the 1-WEE1 X-ray cocrystal structure. Significantly enhanced WEE1 inhibitory selectivity over PLK1 was determined for leading macrocycle 2, which also demonstrated broader kinome-wide selectivity. Patient-derived organoids from colorectal cancer (CRC) peritoneal and liver metastases, treated with 2, demonstrated comparably strong or enhanced anticancer efficacy compared to that of 1. Against patient-matched normal colon vs primary CRC organoids, 2 potently and selectively treated CRC, as well as enhanced DNA damage compared to 1. Finally, the X-ray cocrystal structure of 2 bound to WEE1 validated its computationally predicted bioactive binding mode.

Indexed as

Antineoplastic AgentsCell Cycle ProteinsColorectal NeoplasmsMacrocyclic CompoundsOrganoidsProtein Kinase InhibitorsCrystallography, X-RayHumansModels, MolecularPolo-Like Kinase 1Protein-Tyrosine KinasesPyrazolesStructure-Activity RelationshipAntineoplastic AgentsCell Cycle ProteinsMacrocyclic CompoundsPolo-Like Kinase 1Protein Kinase InhibitorsProtein-Tyrosine KinasesPyrazolesWEE1 protein, human

Identifiers

PMID42623604
PMCPMC13576397

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.