Niche-based screening in multiple myeloma identifies a kinesin-5 inhibitor with improved selectivity over hematopoietic progenitors Journal Article
| Authors: | Chattopadhyay, S.; Stewart, A. L.; Mukherjee, S.; Huang, C.; Hartwell, K. A.; Miller, P. G.; Subramanian, R.; Carmody, L. C.; Yusuf, R. Z.; Sykes, D. B.; Paulk, J.; Vetere, A.; Vallet, S.; Santo, L.; Cirstea, D. D.; Hideshima, T.; Dančík, V.; Majireck, M. M.; Hussain, M. M.; Singh, S.; Quiroz, R.; Iaconelli, J.; Karmacharya, R.; Tolliday, N. J.; Clemons, P. A.; Moore, M.; Stern, A. M.; Shamji, A. F.; Ebert, B. L.; Golub, T. R.; Raje, N. S.; Scadden, D. T.; Schreiber, S. L. |
| Article 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. © 2015 The Authors. |
| Keywords: | controlled study; protein phosphorylation; unclassified drug; oncoprotein; human cell; drug efficacy; antineoplastic agent; phenotype; multiple myeloma; protein targeting; protein binding; cancer screening; drug screening; drug selectivity; cancer resistance; binding site; hematopoietic stem cell; microtubule; coculture; human; priority journal; article; brd 9876; eg5 protein; kinesin 5; bone marrow stroma cell; multiple myeloma cell line |
| Journal Title: | Cell Reports |
| Volume: | 10 |
| Issue: | 5 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2015-02-10 |
| Start Page: | 755 |
| End Page: | 770 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2015.01.017 |
| PROVIDER: | scopus |
| PUBMED: | 25660025 |
| PMCID: | PMC4524791 |
| DOI/URL: | |
| Notes: | Export Date: 2 April 2015 -- Source: Scopus |
