Abstract 5598: First-in-class casein kinase 1 alpha inhibitors for overcoming treatment related resistance in AML and pancreatic cancer

Abstract Background: Inhibition of Casein kinase 1 alpha (CK1α) represents a new attractive concept for the therapy of acute myeloid leukemia (AML). Despite this, currently available small-molecule CK1α inhibitors lack sufficient activity and selectivity to fully exploit the therapeutic potential of CK1α inhibition. We have developed a series of potent and highly selective CK1 kinase inhibitors, including the most effective CK1α inhibitors to date. They inhibit all CK1α/δ/ε isoforms, blocking both CK1δ, ε- and CK1α-dependent processes, which leads to higher efficacy and good tolerability. Targeting of CK1 kinases in resistant cancers is a novel concept - several preclinical studies showed the potential of CK1δ/ε targeting to overcome/avoid resistance - e.g. to potentiate Gemcitabine efficacy in pancreatic cancer, or Enzalutamide in prostate cancer. The precise role of CK1α inhibition is still under evaluation; nevertheless, knockout experiments have revealed that CK1α is essential for survival of most cancer cells and could bring benefit when targeted alone or together with CK1δ/ε. Material and Methods: Cellular target engagement assays, in vitro kinase assays, ADME profiling, testing of in vitro sensitivity to CK1 inhibition and standard-of-care treatments in cell cultures (cell lines, primary AML samples), in vivo efficacy and tolerability studies in mice. Results: First-in-class CK1 inhibitors were developed and evaluated for their potential in preclinical and clinical settings. These inhibitors exhibited sub-nanomolar activity against CK1α, translating into superior on-target activity in cells compared to the previously reported BTX-A51 compound. High efficacy and safety were observed in both in vitro and in vivo AML models, including Venetoclax-resistant AML, underscoring the significant potential of selective CK1α inhibition. A set of biomarkers predicting sensitivity to CK1α inhibitors, including resistance to Venetoclax (a standard-of-care BCL-2 inhibitor), was identified. Additionally, a Gemcitabine-resistant pancreatic cancer model confirmed the efficacy of combining CK1 inhibition with Gemcitabine, resulting in improved outcomes in resistant in vivo models. Proof-of-concept studies are also underway for melanoma and prostate cancer. Conclusions: Our findings highlight the therapeutic potential of selective CK1α inhibition for treating Venetoclax-resistant AML. Furthermore, the data suggest that dual targeting of CK1α/δ/ε may help overcome resistance in specific cancers, such as Gemcitabine-resistant pancreatic cancer and melanoma. This project is co-financed with state support from the Technology Agency of the Czech Republic within the TN Program for the Support of Applied Research, Experimental Development, and Innovation of the National Competence Center (2018 - 2028); project TN02000109 Citation Format: Pavlína Janovská, Tomasz Radaszkiewicz, Martin Čulen, Ingrid Prišticová, Hana Plešingerová, Petra Procházková, Michal Šmída, Daniel Buša, Adriana Ladungová, Lukáš Maier, Štěpán Havel, Kamil Paruch, Jiří Mayer, Alexander Scheer, Vítězslav Bryja. First-in-class casein kinase 1 alpha inhibitors for overcoming treatment related resistance in AML and pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5598.