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

作者：Chattopadhyay Shrikanta^*; Stewart Alison L; Mukherjee Siddhartha; Huang Cherrie; Hartwell Kimberly A; Miller Peter G; Subramanian Radhika; Carmody Leigh C; Yusuf Rushdia Z; Sykes David B; Paulk Joshiawa; Vetere Amedeo; Vallet Sonia; Santo Loredana; Cirstea Diana D; Hideshima Teru; Dancik Vlado; Majireck Max M; Hussain Mahmud M; Singh Shambhavi; Quiroz Ryan; Iaconelli Jonathan; Karmacharya Rakesh; Tolliday Nicola J; Clemons Paul A; Moore Malcolm A S

来源：Cell Reports, 2015, 10(5): 755-770.

DOI：10.1016/j.celrep.2015.01.017

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.

• 出版日期2015-2-10