الوصف: |
CSNK1A1 is a serine/threonine kinase involved in multiple cellular processes, including cell division, beta catenin signaling, and TP53 activation. Inhibition of CSNK1A1 has previously been validated as a therapeutic strategy in hematologic malignancy, and degradation of CSNK1A1 protein is the downstream mechanism of action for lenalidomide in 5q- myelodysplasia (Krönke, et al. Nature. 2015.). However, lenalidomide is inactive in most solid tumor models, thus limiting the study of CSNK1A1 inhibition in other contexts. Analysis of genetic loss-of-function data from the Cancer Dependency Map reveals multiple sensitive models, including lineage-specific enrichment in colorectal and gastric cancer. In an academic-industry collaboration, we a) developed first-in-class potent and selective ATP-competitive CSNK1A1 small molecule inhibitors with preclinical anti-cancer efficacy in vivo, and b) identified FAM83 expression as a key determinant of inhibitor sensitivity. We identified a tetrahydro-pyrrolopyridinone scaffold that was subsequently optimized to yield BAY-888 (CSNK1A1 IC50 4 nM @ 10 μM ATP; 63 nM @ 1 mM ATP) and BAY-204 (CSNK1A1 IC50 2 nM @ 10 μM ATP; 12 nM @ 1 mM ATP). The crystal structure of CSNK1A1 in complex with BAY-888 confirmed compound binding in the ATP binding pocket. Across the PRISM barcoded cell line panel of more than 500 solid tumor cell lines, inhibitors phenocopy the CSNK1A1 shRNA knockdown profile. To determine downstream mediators of CSNK1A1 inhibitor sensitivity, we performed co-IP mass spectrometry following CSNK1A1 pulldown and global phosphoproteomic assays following inhibitor treatment. We identified multiple interacting proteins that are also phosphorylation targets, including FAM83 family members. FAM83 was recently reported to mediate the subcellular localization of CSNK1A1 (Fulcher, et al. Sci Signal. 2018.). Excitingly, the baseline expression of FAM83B and FAM83H correlates with inhibitor and shRNA cell line sensitivity. Modulation of FAM83H expression altered CSNK1A1 localization and sensitivity to CSNK1A1 inhibition. BAY-888 and BAY-204 are orally bioavailable and were evaluated in multiple murine cell line xenograft models. We observed promising efficacy in DLBCL (TMD8) in vivo as well as in multiple FAM83-high solid tumor models, including colorectal (HCT116 and HT29), gastric (IM95), and urothelial cancer (KU19-19). We identified RPS6 phosphorylation as one of the PD biomarkers correlating with efficacy in vivo. In summary, CSNK1A1 is a promising target with anti-tumor efficacy and achievable therapeutic index in preclinical models of FAM83-high solid tumors. Citation Format: Steven M. Corsello, Huajia Zhang, Rajesha Rupaimoole, Volker K. Schulze, Clara Lemos, Kasia B. Handing, Douglas L. Orsi, Mrinal Shekhar, Ulrike Sack, Sven Christian, Wilhelm Bone, Ranad Humeidi, William Colgan, Stephanie Hoyt, Andrew Cherniack, Jens Schroder, Stefan Kaulfuss, Krzysztof Brzezinka, Oliver von Ahsen, Anne Mengel, Roman C. Hillig, Detlev Suelzle, Jeremie Mortier, Caitlin Harrington, Rohith Nagari, Justyna Wierzbinska, Derek Chiang, Georg Beckmann, Meagan Olive, Namrata Udeshi, Annie Apffel, Steven Carr, Philip Lienau, Christian Lechner, Ulf Boemer, Alisha Caliman, David McKinney, Florence Wagner, Dominik Mumberg, Marcus Bauser, Andrea Haegebarth, Knut Eis, Ashley Eheim, Todd R. Golub. Discovery of potent and selective CSNK1A1 inhibitors for solid tumor 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 3588. |