Abstract 2663: Preclinical profiling of BAY 2666605: The first PDE3A-SLFN12 complex inducer for cancer therapy
Authors: Goldoni Silvia , Lange Martin , Kopitz Charlotte , Kaulfuss Stefan , Golfier Sven , Tersteegen Adrian , Bunse Stefanie , Berthold Melanie , Jordan Thibaud , Lienau Philip , Siegel Franziska , Walter Annette , Seidel Henrik , Aquilanti Elisa , Baker Andrew , Wu Xiaoyun , Lee Sooncheol , Gradl Stefan , di Tomaso Emmanuelle , Meyerson Matthew , Eis Knut , Eheim Ashley , Greulich Heidi 
Published: June 2022

Abstract
BAY 2666605, co-developed by the Broad Institute and Bayer Pharmaceuticals, is a selective and potent molecular glue, part of a family of small molecules recently baptized as ‘velcrins’, that induces complex formation between phosphodiesterase 3A (PDE3A) and SLFN12. BAY 2666605 has recently entered a First-in-Human study (NCT04809805) in patients with advanced solid tumors and here we describe its pre-clinical pharmacology profile. DNMDP, the precursor to BAY 2666605, was discovered in a phenotypic screen of genomically annotated cancer cell lines and sensitivity to treatment correlated to high expression of PDE3A (1). Upon treatment, SLFN12 is recruited into a stable complex with PDE3A where its RNase activity is enhanced and required for response (2). BAY 2666605 is a potent complex inducer (EC50 = 7 nM) and cytotoxic in vitro with nanomolar potency (IC50 = 1nM, in the most sensitive cell lines). Cancer cells with high expression of PDE3A and co-expression of SLFN12 are killed by a mechanism independent of PDE3A enzymatic inhibition. PDE3A-SLFN12 binding is required for cytotoxicity. Biomarker-positive lines are enriched in the melanoma lineage and show dose-dependent sensitivity to BAY 2666605 both in vitro and in vivo. Notably, we have consistently observed tumor regression in biomarker-positive melanoma models, including in PDX models (10mg/kg po BID). Based on target expression data from TCGA and tumor arrays, various other tumor types also co-express PDE3A and SLFN12, such as sarcomas and ovarian cancer. To this end, we show that BAY 2666605 inhibits tumor growth of PDX models of sarcoma and ovarian cancer in vivo. BAY 2666605 has excellent brain penetration, making glioblastoma a promising indication. Biomarker-positive GBM models are sensitive to BAY 2666605 both in vitro and in vivo. In a subset of orthotopic GBM models BAY 2666605 treatment has significant impact on survival. In BAY 2666605 treated models we have observed MCL1 downregulation and this biomarker will be evaluated in clinical settings. Our pre-clinical data indicate that BAY 2666605 is a potent anti-tumor agent with first-in-class potential and broad indication space.
1. de Waal et al. Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics, Nat. Chem. Biol. 12, 102-108 (2016) 2. Garvie et al. Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase, Nat. Commun. 12, 4375 (2021)
Citation Format: Silvia Goldoni, Martin Lange, Charlotte Kopitz, Stefan Kaulfuss, Sven Golfier, Adrian Tersteegen, Stefanie Bunse, Melanie Berthold, Thibaud Jordan, Philip Lienau, Franziska Siegel, Annette Walter, Henrik Seidel, Elisa Aquilanti, Andrew Baker, Xiaoyun Wu, Sooncheol Lee, Stefan Gradl, Emmanuelle di Tomaso, Matthew Meyerson, Knut Eis, Ashley Eheim, Heidi Greulich. Preclinical profiling of BAY 2666605: The first PDE3A-SLFN12 complex inducer for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2663.