Assistant Professor of Chemistry Max Majireck was a co-author on a collaborative paper published in the Feb. 10 issue of Cell Reports. “Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors” resulted from a project that involved 33 researchers and 16 different institutional affiliations including Harvard, Columbia and the Broad Institute of Harvard and MIT. Majireck was part of the research team during his postdoctoral research at Harvard and the Broad Institute.
The team searched for compounds that would selectivity inhibit the growth of multiple myeloma cells over other healthy, “normal” cell types like hematopoietic cells, precursor blood cells that can differentiate to become all other blood cell types.
One of the major challenges in treating multiple myeloma is that stromal cells that make up part of the connective tissue in bone marrow can confer drug resistance to the multiple myeloma cells, causing many therapies to become ineffective. To address this challenge, the research team, led by Shrikanta Chattopadhyay of Massachusetts General Hospital and the Broad Institute, screened for compounds that would kill myeloma cells in the presence of bone marrow stroma. This “co-culture” of multiple myeloma and bone marrow stroma cells was developed by Chattopadhyay et al. to closely mimic the niche environment that is found in human patients having this malignancy.
Using this screen, the researchers identified a compound called BRD9876 that overcomes stromal resistance in multiple myeloma by targeting the protein Eg5. They found that BRD9876 inhibits Eg5 in a novel way that enables it to have selectivity for multiple myeloma over hematopoietic blood cells.
Using a process known as medicinal chemistry, Chattopadhyay and a team of chemists led by Majireck collaborated to synthesize analogs of BRD9876 in an attempt to identify the critical molecular features that gave the compound its unique mechanism of action. They found that none of the examined alterations to the molecule were found to improve its selectivity or other drug-like properties.
Thus, while BRD9876 will not become a drug itself, it can be used as a “small-molecule probe” to demonstrate the feasibility of new therapeutic approaches.
Chattopadhyay, the lead author in this study, presented the results of this work and his other research in a fall 2014 Chemistry Department Seminar titled “Niche in a Dish: Using Microenvironment-Based Phenotypic Screening to Discover New Cancer Therapeutics.”
Other prominent authors on the paper include recent Levitt Speaker Siddhartha Mukherjee, author of the Pulitzer Prize-winning The Emperor of all Maladies – A Biography of Cancer, and Majireck’s postdoctoral advisor Stuart Schreiber, the Morris Loeb Professor of Chemistry and Chemical Biology at Harvard University, director of the Center for the Science of Therapeutics at the Broad Institute, and Howard Hughes Medical Institute investigator.
