Abstract 3295: Pharmacological characterization of CYRS1542: A potent and orally available GSPT1 molecular glue degrader for the treatment of neuroendocrine solid cancer with a favorable safety profile

Abstract Neuroendocrine cancers (NECs) are relatively rare compared to other malignancies, but their clinical behavior can be exceptionally aggressive. Two particularly challenging subtypes of NECs, Small Cell Lung Cancer (SCLC) and Neuroendocrine Prostate Cancer (NEPC), are worthy of attention due to their rapid progression, limited treatment options, and high mortality rates. At the molecular level, SCLC and NEPCs necessitate the presence of TP53 and RB1 mutations (Beltran et al., 2016; George et al., 2015). The frequency of TP53 mutations in SCLC is particularly noteworthy, with studies consistently reporting a high incidence (89~92%) (Chen et al., 2022; Sivakumar et al., 2023). A recent study has unveiled intriguing parallels between NECs and hematological malignancies, shedding light on their shared genetic features and analogous patterns of therapeutic susceptibility (Balanis et al., 2019). GSPT1, a translation termination factor, plays a key role in releasing the complete polypeptide from the ribosome. As cancer cells are dependent on translation processes to express elevated levels of oncoproteins, GSPT1 degradation would have lethal consequences. Specific CRBN modulators possess the capability to induce GSPT1 degradation via the ubiquitin-proteasome pathway. GSPT1 degradation leads to a halt in translation termination, activating the Integrated Stress Response (ISR) and subsequently triggering TP53-independent apoptosis. Despite GSPT1 degradation in cancer cells is appealing due to its potential to disrupt the production of critical proteins necessary for cancer cell survival and growth, the challenge lies in doing so without causing excessive harm to normal cells, as GSPT1 is also indispensable for their vital cellular functions. Remarkably, the ongoing development of GSPT1-targeted agents in clinical trials has raised intriguing questions about the mechanisms by which a therapeutic index can be established. Recently, we have identified CYRS1542 as an orally bioavailable GSPT1 molecular glue degrader (MGD) (Joo et al., 2023). Here, we present a pharmacological characterization of CYRS1542 as a potent and orally bioavailable GSPT1 MGD with the ability to effectively treat aggressive neuroendocrine cancers. In various NEC in vivo models, including an orthotopic model, CYRS1542 demonstrated dose-dependent and excellent anti-tumor efficacy comparable to the clinical stage GSPT1 MGD. Furthermore, it demonstrates improved safety profiles in a broad spectrum of normal cells, resulting in a higher therapeutic index compared to the clinical GSPT1 MGD. Citation Format: Min Sung Joo, JaeYung Lee, Joonhyung Lee, Eun-Jung Kim, Seogbeom Song, Jeonghyeon Lee, Joonwoo Nam, Heuijoon Park, Jaewoo Park, Keon Wook Kang, Wooseok Han. Pharmacological characterization of CYRS1542: A potent and orally available GSPT1 molecular glue degrader for the treatment of neuroendocrine solid cancer with a favorable safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3295.