Evidence map›Paper›PMID 28985505›Full record

ArticleMolecular cell2017

Combined CRISPRi/a-Based Chemical Genetic Screens Reveal that Rigosertib Is a Microtubule-Destabilizing Agent.

Marco Jost, Yuwen Chen, Luke A Gilbert, Max A Horlbeck, Lenno Krenning, Grégory Menchon, Ankit Rai, Min Y Cho, Jacob J Stern, Andrea E Prota and 5 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular cell, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 120 papers.

0numbers the graph read from it
0cells of the map it votes in
120citing 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

120 citing papers in PubMed.

  1. Article
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  12. The Anthelmintic Activity ofPathogens (Basel, Switzerland) · 2025
    Article
  13. Article
  14. Article
  15. Review
  16. Review
  17. Review
  18. Article
  19. Article
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60 more citing papers are in PubMed but not listed here.

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

15 authors.

Marco JostDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Center for RNA Systems Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
Yuwen ChenDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Center for RNA Systems Biology, University of California, San Francisco, San Francisco, CA 94158, USA.
Luke A GilbertDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Center for RNA Systems Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA.
Max A HorlbeckDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Center for RNA Systems Biology, University of California, San Francisco, San Francisco, CA 94158, USA.
Lenno KrenningHubrecht Institute - KNAW and University Medical Center Utrecht, 3584CT Utrecht, the Netherlands.
Grégory MenchonLaboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland.
Ankit RaiCell Biology, Department of Biology, Faculty of Science, Utrecht University, 3548CH Utrecht, the Netherlands.
Min Y ChoDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Center for RNA Systems Biology, University of California, San Francisco, San Francisco, CA 94158, USA.
Jacob J SternDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Center for RNA Systems Biology, University of California, San Francisco, San Francisco, CA 94158, USA.
Andrea E ProtaLaboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland.
Martin KampmannDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Center for RNA Systems Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA.
Anna AkhmanovaCell Biology, Department of Biology, Faculty of Science, Utrecht University, 3548CH Utrecht, the Netherlands.
Michel O SteinmetzLaboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland; Biozentrum, University of Basel, 4056 Basel, Switzerland.
Marvin E TanenbaumHubrecht Institute - KNAW and University Medical Center Utrecht, 3584CT Utrecht, the Netherlands. Electronic address: m.tanenbaum@hubrecht.eu.
Jonathan S WeissmanDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Center for RNA Systems Biology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: jonathan.weissman@ucsf.edu.

Funding

MEDICAL SCIENTIST TRAINING PROGRAMT32GM007618 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ANDERSON, MARK S · 1985 to 2020
$29.6M
PROJECT 3P50GM102706 · NIGMS · UNIVERSITY OF CALIFORNIA BERKELEY · PI CATE, JAMIE H · 2012 to 2016
$9.5M
The Cancer Target Discovery and Development Network at UCSFU01CA217882 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BANDYOPADHYAY, SOURAV, BIVONA, TREVER G · 2017 to 2021
$5.2M
Bay Area Cancer Target Discovery and Development NetworkU01CA168370 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MCCORMICK, FRANK PATRICK, MCMANUS, MICHAEL T · 2012 to 2016
$3.9M
Integrative Program in Complex Biological System (ipCBS)T32EB009383 · NIBIB · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MARSHALL, WALLACE, WEINER, ORION D · 2009 to 2022
$3.2M
Harnessing CRISPR for Targeted and Inducible Epigenomic ReprogrammingR01DA036858 · NIDA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI LIM, WENDELL A, QI, LEI STANLEY · 2013 to 2017
$2.9M
A functional genomics approach to determine the mechanism of cellular response to new anti-cancer R00CA204602 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GILBERT, LUKE · 2017 to 2019
$747k
Systematic Genome-Wide Characterization of Iron HomeostasisF32GM116331 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI JOST, MARCO · 2015 to 2017
$162k
A functional genomics approach to determine the mechanism of cellular response to new anti-cancer drugsK99CA204602 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GILBERT, LUKE · 2016 to 2016
$139k
Stress response networks in cancer: systematic mapping and therapeutic potentialK99CA181494 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KAMPMANN, MARTIN · 2014 to 2014
$139k
Howard Hughes Medical InstituteNCI NIH HHS K99 CA181494NCI NIH HHS K99 CA204602NCI NIH HHS R00 CA204602NCI NIH HHS U01 CA168370NCI NIH HHS U01 CA217882NIBIB NIH HHS T32 EB009383NIDA NIH HHS R01 DA036858NIGMS NIH HHS F32 GM116331NIGMS NIH HHS P50 GM102706NIGMS NIH HHS T32 GM007618
6 · The paper itself

Abstract

Chemical libraries paired with phenotypic screens can now readily identify compounds with therapeutic potential. A central limitation to exploiting these compounds, however, has been in identifying their relevant cellular targets. Here, we present a two-tiered CRISPR-mediated chemical-genetic strategy for target identification: combined genome-wide knockdown and overexpression screening as well as focused, comparative chemical-genetic profiling. Application of these strategies to rigosertib, a drug in phase 3 clinical trials for high-risk myelodysplastic syndrome whose molecular target had remained controversial, pointed singularly to microtubules as rigosertib's target. We showed that rigosertib indeed directly binds to and destabilizes microtubules using cell biological, in vitro, and structural approaches. Finally, expression of tubulin with a structure-guided mutation in the rigosertib-binding pocket conferred resistance to rigosertib, establishing that rigosertib kills cancer cells by destabilizing microtubules. These results demonstrate the power of our chemical-genetic screening strategies for pinpointing the physiologically relevant targets of chemical agents.

Indexed as

Gene Expression Regulation, NeoplasticAntineoplastic AgentsColchicineCRISPR-Cas SystemsDrug Resistance, NeoplasmGenetic TestingGenetic VectorsGlycineHeLa CellsHumansK562 CellsKinesinsLentivirusMicrotubulesMutationMyelodysplastic SyndromesAntineoplastic AgentsColchicineGlycineKIF2C protein, humanKinesinsON 01910Recombinant Fusion ProteinsRNA, Guide, CRISPR-Cas SystemsSmall Molecule LibrariesSulfonesTubulinTubulin ModulatorsVinblastinechemical geneticsCRISPRaCRISPRidrug mechanism of actiondrug target identificationgenome-wide CRISPR screeningmicrotubulesrigosertib

Identifiers

PMID28985505
PMCPMC5640507

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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.