Niche-Based screening in multiple myeloma identifies a kinesin-5 inhibitor with improved selectivity over hematopoietic progenitors

Shrikanta Chattopadhyay*, Alison L. Stewart, Siddhartha Mukherjee, Cherrie Huang, Kimberly A. Hartwell, Peter G. Miller, Radhika Subramanian, Leigh C. Carmody, Rushdia Z. Yusuf, David B. Sykes, Joshiawa Paulk, Amedeo Vetere, Sonia Vallet, Loredana Santo, Diana D. Cirstea, Teru Hideshima, Vlado Dančík, Max M. Majireck, Mahmud M. Hussain, Shambhavi SinghRyan Quiroz, Jonathan Iaconelli, Rakesh Karmacharya, Nicola J. Tolliday, Paul A. Clemons, Malcolm A.S. Moore, Andrew M. Stern, Alykhan F. Shamji, Benjamin L. Ebert, Todd R. Golub, Noopur S. Raje, David T. Scadden, Stuart L. Schreiber

*Corresponding author for this work

Research output: Journal article (peer-reviewed)Journal article

20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)755-770
Number of pages16
JournalCell Reports
Volume10
Issue number5
DOIs
Publication statusPublished - 10 Feb 2015
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology

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