Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

  • Cell Rep. 2015 Feb 10;10(5):755-770. doi: 10.1016/j.celrep.2015.01.017.
Shrikanta Chattopadhyay  1 ,  Alison L Stewart  2 ,  Siddhartha Mukherjee  3 ,  Cherrie Huang  4 ,  Kimberly A Hartwell  5 ,  Peter G Miller  6 ,  Radhika Subramanian  7 ,  Leigh C Carmody  2 ,  Rushdia Z Yusuf  8 ,  David B Sykes  8 ,  Joshiawa Paulk  9 ,  Amedeo Vetere  2 ,  Sonia Vallet  10 ,  Loredana Santo  10 ,  Diana D Cirstea  11 ,  Teru Hideshima  11 ,  Vlado Dančík  2 ,  Max M Majireck  9 ,  Mahmud M Hussain  12 ,  Shambhavi Singh  9 ,  Ryan Quiroz  13 ,  Jonathan Iaconelli  14 ,  Rakesh Karmacharya  15 ,  Nicola J Tolliday  2 ,  Paul A Clemons  2 ,  Malcolm A S Moore  16 ,  Andrew M Stern  17 ,  Alykhan F Shamji  2 ,  Benjamin L Ebert  18 ,  Todd R Golub  19 ,  Noopur S Raje  10 ,  David T Scadden  20 ,  Stuart L Schreiber  21
Affiliations
  • 1. 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: [email protected].
  • 2. Center for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
  • 3. Department of Medicine and Irving Cancer Research Center, Columbia University School of Medicine, New York, NY 10032, USA.
  • 4. 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.
  • 5. Cancer Program, Broad Institute, Cambridge, MA 02142, USA.
  • 6. Harvard Medical School, Boston, MA 02115, USA; Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 7. Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA.
  • 8. Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 9. Center for the Science of Therapeutics / Center for the Development of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Harvard University, Cambridge, MA 02138, USA.
  • 10. Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 11. Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 12. 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.
  • 13. 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.
  • 14. 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.
  • 15. 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.
  • 16. Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 17. 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.
  • 18. Dana-Farber Cancer Institute, Boston, MA 02115, USA; Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 19. 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.
  • 20. 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.
  • 21. 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: [email protected].
PMID: 25660025 DOI: 10.1016/j.celrep.2015.01.017
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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