ArticleCell reports2015
Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors.
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Article in Cell reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18citing papers in PubMed
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Who cites it
18 citing papers in PubMed.
- Beyond the epithelium: multicellular niches in lung regeneration and disease.American journal of physiology. Lung cellular and molecular physiology · 2026Review
- Kinesin Spindle Protein (KIF11) in Mitosis and Cancer.International journal of molecular sciences · 2025Review
- Selective molecular inhibition of the HDAC6 ZnF-UBP binding domain impairs multiple myeloma cell function.Cell death discovery · 2025Article
- An "In Schizo" Evaluation System to Screen for Human Kinesin-5 Inhibitors.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Drug resistance dependent on allostery: A P-loop rigor Eg5 mutant exhibits resistance to allosteric inhibition by STLC.Frontiers in oncology · 2022Article
- Oncogene-Induced Reprogramming in Acute Lymphoblastic Leukemia: Towards Targeted Therapy of Leukemia-Initiating Cells.Cancers · 2021Review
- The nature of cell division forces in epithelial monolayers.The Journal of cell biology · 2021Article
- Targeting the Id1-Kif11 Axis in Triple-Negative Breast Cancer Using Combination Therapy.Biomolecules · 2020Article
- HSP70 regulates Eg5 distribution within the mitotic spindle and modulates the cytotoxicity of Eg5 inhibitors.Cell death & disease · 2020Article
- Structure of Microtubule-Trapped Human Kinesin-5 and Its Mechanism of Inhibition Revealed Using Cryoelectron Microscopy.Structure (London, England : 1993) · 2020Article
- Modeling the human bone marrow niche in mice: From host bone marrow engraftment to bioengineering approaches.The Journal of experimental medicine · 2018Review
- Cancer drug therapy and stochastic modeling of "nano-motors".International journal of nanomedicine · 2018Article
- Structural basis of human kinesin-8 function and inhibition.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Review
- Eg5 Inhibitors Have Contrasting Effects on Microtubule Stability and Metaphase Spindle Integrity.ACS chemical biology · 2017Article
- High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells.The Journal of clinical investigation · 2016Article
- Article
- Advances in discovering small molecules to probe protein function in a systems context.Current opinion in chemical biology · 2016Review
Corrections and comments
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Authors and funding
33 authors.
Shrikanta ChattopadhyayCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: schattopadhyay@partners.org.
Alison L StewartCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
Siddhartha MukherjeeDepartment of Medicine and Irving Cancer Research Center, Columbia University School of Medicine, New York, NY 10032, USA.
Cherrie HuangCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Kimberly A HartwellCancer Program, Broad Institute, Cambridge, MA 02142, USA.
Peter G MillerHarvard Medical School, Boston, MA 02115, USA; Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Radhika SubramanianChemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA.
Leigh C CarmodyCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
Rushdia Z YusufCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
David B SykesCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
Joshiawa PaulkCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Harvard University, Cambridge, MA 02138, USA.
Amedeo VetereCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
Sonia ValletCancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
Loredana SantoCancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
Diana D CirsteaDana-Farber Cancer Institute, Boston, MA 02115, USA.
Teru HideshimaDana-Farber Cancer Institute, Boston, MA 02115, USA.
Vlado DančíkCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
Max M MajireckCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Harvard University, Cambridge, MA 02138, USA.
Mahmud M HussainCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Broad Institute, Cambridge, MA 02142, USA.
Shambhavi SinghCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Harvard University, Cambridge, MA 02138, USA.
Ryan QuirozCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; University of California, Los Angeles, Los Angeles, CA 90095, USA.
Jonathan IaconelliCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Rakesh KarmacharyaCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Schizophrenia and Bipolar Disorder Program, McLean Hospital, Belmont, MA 02478, USA.
Nicola J TollidayCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
Paul A ClemonsCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
Malcolm A S MooreCell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Andrew M SternCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Alykhan F ShamjiCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
Benjamin L EbertDana-Farber Cancer Institute, Boston, MA 02115, USA; Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Todd R GolubCancer Program, Broad Institute, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA; Howard Hughes Medical Institute, Broad Institute, Cambridge, MA 02142, USA.
Noopur S RajeCancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
David T ScaddenCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Harvard University, Cambridge, MA 02138, USA.
Stuart L SchreiberCenter for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Broad Institute, Cambridge, MA 02142, USA. Electronic address: stuart_schreiber@harvard.edu.
Funding
Medical Scientist Training ProgramT32GM007753 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI WALENSKY, LOREN DAVID · 1985 to 2021
$50.0MTrageting the Multiple Myeloma EpigenomeP50CA100707 · NCI · DANA-FARBER CANCER INSTITUTE · PI ANDERSON, KENNETH C., MUNSHI, NIKHIL C. · 2003 to 2023
$45.0MSYNTHESIS OF MATERIALS WITH PHYSIOLOGICAL PROPERTIESR01GM038627 · NIGMS · YALE UNIVERSITY · PI SCHREIBER, STUART L · 1987 to 2017
$10.5MMicroenvironmental control of progenitors in organ dysfunction and repairU01HL100402 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI KIM, CARLA F., SCADDEN, DAVID T · 2009 to 2015
$8.5MTarget ID (3 of 4)RL1HG004671 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI SCHREIBER, STUART L · 2007 to 2011
$5.8MStromal Regulation of Bone MetastasisU54CA163191 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KALLURI, RAGHU · 2011 to 2015
$4.8MFUNCTIONAL ISOLATION OF HUMAN HEMATOPOIETIC STEM CELLSR01DK050234 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI SCADDEN, DAVID T · 1995 to 2012
$3.7MWnt/GSK3/beta Catenin Signaling as a Target for Treatment of Bipolar DisorderK08MH086846 · NIMH · MCLEAN HOSPITAL · PI KARMACHARYA, RAKESH · 2010 to 2014
$901kTargeting Metastasis Induced by Mesenchymal Stem Cells in the Tumor StromaK08CA158149 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI CHATTOPADHYAY, SHRIKANTA · 2011 to 2015
$890kNCI NIH HHS K08 CA158149NCI NIH HHS P50 CA100707NCI NIH HHS U54 CA163191NHGRI NIH HHS RL1 HG004671NHLBI NIH HHS U01 HL100402NIDDK NIH HHS R01 DK050234NIGMS NIH HHS R01 GM038627NIGMS NIH HHS T32 GM007753NIMH NIH HHS K08 MH086846
Abstract
Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to BRD9876's mode of action. Thus, differences in Eg5-microtubule binding between malignant and normal blood cells may be exploited to treat multiple myeloma. Additional steps are required for further therapeutic development, but our results indicate that unbiased chemical biology approaches can identify therapeutic strategies unanticipated by prior knowledge of protein targets.
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