title: Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors.
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.
authors: Center 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.
authors: Shrikanta
authors: S
authors: Chattopadhyay
authors: Center for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
authors: Alison L
authors: AL
authors: Stewart
authors: Department of Medicine and Irving Cancer Research Center, Columbia University School of Medicine, New York, NY 10032, USA.
authors: Siddhartha
authors: S
authors: Mukherjee
authors: Center 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.
authors: Cherrie
authors: C
authors: Huang
authors: Cancer Program, Broad Institute, Cambridge, MA 02142, USA.
authors: Kimberly A
authors: KA
authors: Hartwell
authors: Harvard Medical School, Boston, MA 02115, USA; Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Peter G
authors: PG
authors: Miller
authors: Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA.
authors: Radhika
authors: R
authors: Subramanian
authors: Center for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
authors: Leigh C
authors: LC
authors: Carmody
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Rushdia Z
authors: RZ
authors: Yusuf
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: David B
authors: DB
authors: Sykes
authors: Center for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Harvard University, Cambridge, MA 02138, USA.
authors: Joshiawa
authors: J
authors: Paulk
authors: Center for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
authors: Amedeo
authors: A
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authors: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Sonia
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authors: Vallet
authors: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Loredana
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authors: Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Diana D
authors: DD
authors: Cirstea
authors: Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Teru
authors: T
authors: Hideshima
authors: Center for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
authors: Vlado
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authors: Dančík
authors: Center for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Harvard University, Cambridge, MA 02138, USA.
authors: Max M
authors: MM
authors: Majireck
authors: Center 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.
authors: Mahmud M
authors: MM
authors: Hussain
authors: Center for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Harvard University, Cambridge, MA 02138, USA.
authors: Shambhavi
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authors: Center 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.
authors: Ryan
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authors: Center 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.
authors: Jonathan
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authors: Iaconelli
authors: Center 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.
authors: Rakesh
authors: R
authors: Karmacharya
authors: Center for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
authors: Nicola J
authors: NJ
authors: Tolliday
authors: Center for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
authors: Paul A
authors: PA
authors: Clemons
authors: Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Malcolm A S
authors: MAS
authors: Moore
authors: Center 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.
authors: Andrew M
authors: AM
authors: Stern
authors: Center for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
authors: Alykhan F
authors: AF
authors: Shamji
authors: Dana-Farber Cancer Institute, Boston, MA 02115, USA; Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Benjamin L
authors: BL
authors: Ebert
authors: Cancer 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.
authors: Todd R
authors: TR
authors: Golub
authors: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Noopur S
authors: NS
authors: Raje
authors: Center 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.
authors: David T
authors: DT
authors: Scadden
authors: Center 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.
authors: Stuart L
authors: SL
authors: Schreiber