Abstract 5880: Small-molecule modulators of PDE3/SLFN12 to kill cancer cells

We have previously reported 1 our results with a small molecule called DNMDP which kills certain cancer cells by modulating the interaction of PDE3A and Schlafen 12 (SLFN12), a more recently discovered protein of unknown function. While DNMDP selectively inhibits PDE3, most PDE3 inhibitors have no cell killing effects and in fact rescue cancer cells from DNMDP-induced death. DNMDP is not suitable for advanced studies due to structural liabilities. Optimization of DNMDP to both increase activity and improve pharmacokinetic properties resulted in enantiomerically pure, low molecular weight, metabolically stable compounds which are active at low doses in animal models of cervical cancer and melanoma. While these compounds are selective PDE3A inhibitors and their biochemical activity mirrors their cellular activity, the activity of the compounds results not from PDE3 inhibition and increased cAMP levels, but from increased compound-induced binding of PDE3A to SLFN12, which most PDE3 inhibitors do not effect. Our results suggest that small molecule modulators of PDE3/SLFN12 binding may provide a novel treatment for the treatment of certain cancers. 1 Nat. Chem. Bio. 2016, 12, 102-108. Citation Format: Timothy A. Lewis, Luc de Waal, Xiaoyun Wu, Manuel Ellerman, Charlotte Kopitz, Antje Wengner, Knut Eis, Martin Lange, Adrian Tersteegen, Philip Lienau, Heidi Greulich, Matthew Meyerson. Small-molecule modulators of PDE3/SLFN12 to kill cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5880.