LAUSR

Molecular glue degrader (MGD) is an emerging therapeutic strategy offering an exciting alternative to traditional small molecules exploring new target space. These small molecules interact with the ubiquitin-proteasome system (UPS) to promote degradation of protein of interest (POI), especially those considered to be challenging targets (e.g., GSPT1, VAV1, WIZ, BCL6, STAT6, IKZFs). In fact, clinical proof of concept has been obtained with immunomodulatory drugs such as thalidomide, lenalidomide and pomalidomide, which degrade IKZF1/IKZF3. GSPT1 (G1 to S phase transition protein 1) is a challenging POI engaged in regulation of cell cycle progression at the G1-S transition and in mRNA translation termination, playing a key role in cancer progression. Recently, encouraging results have been obtained with different modalities targeting GSPT1. GSPT1 degrader antibody conjugates are now in clinical trials for breast cancer (ORM-5029) and AML (BMS-986497/ORM-6151). Of interest, an orally active GSPT1 degrader (MRT-2359) is in Phase 2 trial for MYC-driven tumors including NSCLC and SCLC, with 2 PR, 1 SD in six biomarker positive patients (September 2024). Safety profile at this stage supports further clinical development. Preclinically, MRT-2359 is a potent GSPT1 degrader with nanomolar in vitro IC50 and oral bioavailability of ∼50%. It shows anti-tumor activity in NSCLC xenograft model starting at 1 mg/kg PO, QD. These encouraging results have prompted us to explore a series of GSPT1 MGDs.In the present study, we describe the discovery of a series of novel, potent and orally active GSPT1 MGD targeting tumors with high GSPT1 expression. In the BT-747 human breast cancer cell assay, IC50s for serval compounds are between 5 - 50 nM, in the same range as that of MRT-2359 and other comparators in the same assay. Significant GSPT1 protein degradation of these compounds is observed showing on-target mechanism of action, without affecting protein degradation in a panel of proteins. A representative compound in the series shows a promising pharmacokinetic profile (PO at 3 mg/kg; IV at 1 mg/kg) with an oral bioavailability of 55 %, Cmax of 0.78 µM, t1/2 of 2.3 hour and Vdss of 1.82 L/kg in mouse. This compound demonstrates in vivo efficacy in CDX model with a favorable profile comparable to that of MRT-2359. In summary, a series of orally active GSPT1 degraders have been discovered with preclinical profile suitable for further development to manage cancers with high GSPT1 expression. Chi-Chung Chan, Chun-Sing Li, Lihong Hu, Wenxi Li, Zhenzhen Zhu, Shuhui Chen. Discovery of novel, potent and orally active GSPT1 molecular glue degraders [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 393.