Model of DNMDP-induced complex formation between PDE3A and SLFN12.
Wu, et al., J Biol Chem, 2020. Mechanistic insights into cancer cell killing through interaction of phosphodiesterase 3A and schlafen family member 12.
Wu, et al., J Biol Chem, 2020. Mechanistic insights into cancer cell killing through interaction of phosphodiesterase 3A and schlafen family member 12.
Genome-inspired Cancer Drug Discovery
Cancer is a disease of the genome. Cancer cells differ from normal cells because they possess alterations in their genome, both “driver” alterations that cause cancer and “passenger” alterations that arise from the same mutational processes that generate the driver alterations. Both drivers and passengers, representing distinctions between cancer cells and normal cells, can become targets for effective anti-cancer therapies. Thus, to know the genome of cancer allows us to find its vulnerabilities, and by finding cancer’s vulnerabilities, we have the opportunity to build therapies to defeat it.
Currently there is no therapeutic approach for many of the most common genome alterations—among them alterations in Myc, Ras, p53 genes and telomerase, the most targeted alterations in all of cancer. Genomic profiling of individual cancer types is enabling discovery of targeted therapies that are both more efficacious and less toxic than their predecessors. We are applying this concept of “genome-inspired cancer therapy” to develop new modes of cancer treatment.
In separate work using a predictive chemogenomics approach, we found a correlation between sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP) and expression of PDE3A in hundreds of cancer cell lines. We further showed that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), that aryl hydrocarbon receptor interacting protein (AIP) is required for this interaction, and that depletion of either PDE3A or SLFN12 reduces sensitivity to DNMDP (de Waal, et al., 2016; Wu, et al., 2020). These results findings implicate PDE3A modulators as candidate therapeutic agents.
Currently there is no therapeutic approach for many of the most common genome alterations—among them alterations in Myc, Ras, p53 genes and telomerase, the most targeted alterations in all of cancer. Genomic profiling of individual cancer types is enabling discovery of targeted therapies that are both more efficacious and less toxic than their predecessors. We are applying this concept of “genome-inspired cancer therapy” to develop new modes of cancer treatment.
In separate work using a predictive chemogenomics approach, we found a correlation between sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP) and expression of PDE3A in hundreds of cancer cell lines. We further showed that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), that aryl hydrocarbon receptor interacting protein (AIP) is required for this interaction, and that depletion of either PDE3A or SLFN12 reduces sensitivity to DNMDP (de Waal, et al., 2016; Wu, et al., 2020). These results findings implicate PDE3A modulators as candidate therapeutic agents.