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Cell Rep DOI:10.1016/j.celrep.2015.01.017

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

Publication TypeJournal Article
Year of Publication2015
AuthorsChattopadhyay, S, Stewart, AL, Mukherjee, S, Huang, C, Hartwell, KA, Miller, PG, Subramanian, R, Carmody, LC, Yusuf, RZ, Sykes, DB, Paulk, J, Vetere, A, Vallet, S, Santo, L, Cirstea, DD, Hideshima, T, Dančík, V, Majireck, MM, Hussain, MM, Singh, S, Quiroz, R, Iaconelli, J, Karmacharya, R, Tolliday, NJ, Clemons, PA, Moore, MAS, Stern, AM, Shamji, AF, Ebert, BL, Golub, TR, Raje, NS, Scadden, DT, Schreiber, SL
JournalCell Rep
Date Published2015 Feb 04
ISSN2211-1247
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S2211-1247(15)00030-3
DOI10.1016/j.celrep.2015.01.017
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25660025?dopt=Abstract

Alternate JournalCell Rep
PubMed ID25660025
PubMed Central IDPMC4524791
Grant ListU54 CA163191 / CA / NCI NIH HHS / United States
K08 CA158149 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R01 GM038627 / GM / NIGMS NIH HHS / United States
K08 MH086846 / MH / NIMH NIH HHS / United States
U01 HL100402 / HL / NHLBI NIH HHS / United States
P50 CA100707 / CA / NCI NIH HHS / United States
R01 DK050234 / DK / NIDDK NIH HHS / United States
RL1 HG004671 / HG / NHGRI NIH HHS / United States