Abstract 4950: Discovery of potent and selective CK1α molecular degrader with a favorable safety profile for acute myeloid leukemia and solid tumors

Abstract CK1α, an isoform of casein kinase 1 (CK1), promotes tumor growth by enhancing negative effects of MDM2 and MDMX on p53. Unlike other cancer types, the frequency of TP53 mutations is relatively low (&amp;lt; 20%) in acute myeloid leukemia (AML). Therefore, promoting apoptosis by activation of p53 pathway has been a promising strategy for treatment of AML with wild-type (WT) TP53. However, preclinical activities of p53 activators have not been fully translated into clinic, partly due to their on-target hematological toxicities. We hypothesized that inhibition of CK1α can be an alternative strategy. To develop a small molecule targeting CK1α, we identified a novel CK1α-selective molecular glue degrader (MGD), PIN-A1 through screening of compounds hijacking cereblon (CRBN) E3 ligase. Here, we report its robust pharmacological activities in various preclinical AML models as a single agent or in combination with other targeted therapies along with its superior safety profile to MDM2 inhibitors. First, we demonstrated PIN-A1 can form a ternary complex with CK1α and CRBN using TR-FRET assay. Selective degradation of CK1α by PIN-A1 was also confirmed by global proteomics analysis. PIN-A1 induced rapid degradation of CK1α in human AML MV-4-11 cells harboring WT TP53, followed by increasing the level of p53 protein and its downstream target genes, ultimately leading to apoptotic cell death. Consistent with these results, preferential sensitivity of AML cells with WT TP53 to the CK1α degrader was demonstrated in screening assay of broad panel of liquid cancer cell lines. When combined with other targeted therapies agents used for AML, PIN-A1 displayed strong synergistic effects in cell killing. To evaluate its pharmacological activity in vivo, PIN-A1 was tested in a xenograft model engrafted with MV-4-11 and a dissemination model of MOLM-14, respectively. Systemic administration of PIN-A1 alone resulted in robust antitumor activity consistent with &amp;gt; 90% CK1α degradation in tumor tissues, comparably achieved at a much lower dose in combo treatments. Importantly, animals remained tumor-free (5/8) in the MV-4-11 model or prolonged survival in the disseminated model even after they were no longer on the combination treatment of PIN-A1 with a targeted agent X. Lastly, while PIN-A1 had negligible effects on the viability of human PBMC with minimal activation of the p53 pathway at an efficacious dose range for MV-4-11 (Therapeutic index= 8,333), agent X induced p53 pathway and enhanced anti-leukemic activity to a similar extent in two cell types (Therapeutic index=4). Also, we found that the combination treatment of PIN-A1 with agent X had a substantial effect on several solid tumors driven by enhancing the stability and activity of p53. In summary, these results suggest that a CK1α MGD with its favorable safety profile has a potential to become an effective treatment option for advanced AML and solid tumors. Citation Format: Jinuk Kong, Jisu Park, Heekyu Lee, Hyunseok Kang, Deokjae Lee, Hyunsun Jo. Discovery of potent and selective CK1α molecular degrader with a favorable safety profile for acute myeloid leukemia and solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4950.

Topic: Protein Degradation and Inhibitors
Subfield: Molecular Biology
Field: Biochemistry, Genetics and Molecular Biology
Domain: Life Sciences