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” alteration, each of which can become targets for effective anti-cancer therapies.
Currently there is no therapeutic approach for many of the most common genome alterations—among them alterations in Myc, p53 genes and telomerase.
Our work on telomerase has led to a clear analysis of the indications for telomerase inhibition in the treatment of glioblastoma based on cell line and xenograft dependency (Aquilanti et al., 2023). We are also working to improve treatment for EGFR mutant lung cancer, focusing initially on exon 20 insertion mutants (beginning with Greulich et al., 2005). Together with colleagues at Bayer, we have developed BAY2927088, currently in clinical trials (https://clinicaltrials.gov/study/NCT05099172).
We are also working on molecular glues including compounds to re-localize cellular proteins—watch this space for more! In separate work using a predictive chemogenomics approach, we identified a cancer cytotoxic compound, 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP). We showed that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), and that depletion of either PDE3A or SLFN12 reduces sensitivity to DNMDP (de Waal, et al., 2016; Wu, et al., 2020; Lee et al., 2022). BAY2666605, a PDE3A-SLFN12 complex inducer, is undergoing clinical trial (https://clinicaltrials.gov/study/NCT04809805).
Currently there is no therapeutic approach for many of the most common genome alterations—among them alterations in Myc, p53 genes and telomerase.
Our work on telomerase has led to a clear analysis of the indications for telomerase inhibition in the treatment of glioblastoma based on cell line and xenograft dependency (Aquilanti et al., 2023). We are also working to improve treatment for EGFR mutant lung cancer, focusing initially on exon 20 insertion mutants (beginning with Greulich et al., 2005). Together with colleagues at Bayer, we have developed BAY2927088, currently in clinical trials (https://clinicaltrials.gov/study/NCT05099172).
We are also working on molecular glues including compounds to re-localize cellular proteins—watch this space for more! In separate work using a predictive chemogenomics approach, we identified a cancer cytotoxic compound, 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP). We showed that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), and that depletion of either PDE3A or SLFN12 reduces sensitivity to DNMDP (de Waal, et al., 2016; Wu, et al., 2020; Lee et al., 2022). BAY2666605, a PDE3A-SLFN12 complex inducer, is undergoing clinical trial (https://clinicaltrials.gov/study/NCT04809805).