A new study co-authored by Professor of Chemistry John Porco along with collaborators at the Whitehead Institute has clarified how a naturally occurring anticancer molecule helps to fight tumor growth. The researchers found that rocaglamide A, an inhibitor of translation initiation, is a strong inhibitor of Heat Shock Factor 1 (HSF1) activation. HSF1 inhibitors have received significant attention for their potential role in the rapid development of anticancer drugs with completely new modes of action.
HSF1 is the master regulator of the Heat Shock Response (HSR) in cells, which attempts to maintain protein homeostasis during times of proteotoxic cellular stress. This stress results in the accumulation of misfolded proteins and has been identified as a cause of cancerous cells. Experimenting with a number of chemical and genetic approaches to determine how information about a cell’s metabolic state is conveyed, the researchers earlier established that HSF1, which is centrally positioned to regulate cellular proliferation, functions as the primary translator (transducer) of this information. The new study, published in the journal Science, found that rocaglamide A, a naturally occurring anticancer agent, effectively inhibits HSF1 activation.
The study is the latest product of a three-year research grant from the National Institutes of Health awarded to Porco and Dr. Luke Whitesell, senior scientist in the laboratory of Prof. Susan Lundquist at MIT’s Whitehead Institute. This combined biology/chemistry team came together expressly to identify highly potent and selective HSF1 inhibitor probes with useful activity in vivo.
Whitesell and his colleagues have shown that HSF1 is co-opted by tumor cells to promote their own survival at the expense of their hosts; their ongoing research has focused on explaining how the HSF1 coordinates this activity during malignancy, how it might relate to a classic HSR, and whether it impacts human cancer. Whitesell enlisted the Porco laboratory for its expertise in the synthesis of complex natural products and derivatives. The unique photocycloaddition methodology, developed by the Porco laboratory for the synthesis of various targets, is the basis of the medicinal chemistry efforts in the NIH award to optimize these compounds as HSF-1 inhibitors.
To identify the transcriptional effects of modulating translational activity in malignant cells in the present study, the researchers used integrated chemical and genetic approaches, including a gene signature–based genetic and chemical screen of more than 600,000 gene expression profiles (LINCS database) and an independent, reporter-based chemical screen of more than 300,000 compounds. A lead compound was tested in several cell lines unified by their increased dependence on HSF1 activation for growth and survival, and in an in vivo cancer model. The screens identified rocaglamide A, an inhibitor of translation initiation, as the strongest inhibitor of HSF1 activation. Cell-based cancer models characterized by high dependence on HSF1 activation for growth and survival also were highly sensitive to the rocaglate rohinitib (RHT), an analog of rocaglamide A, as were cells derived from diverse hematopoietic malignancies.