Monte Rosa Therapeutics Showcases Preclinical Data on Cyclin E1 Molecular Glue Degraders for CCNE1-Amplified Tumors at 36th EORTC-NCI-AACR Symposium

Monte Rosa Therapeutics, Inc., a biotechnology company specializing in molecular glue degrader (MGD)-based medicines, is set to present groundbreaking preclinical data at the 36th EORTC-NCI-AACR Symposium (ENA 2024) in Barcelona, Spain. The company will showcase the potential of its Cyclin E1 (CCNE1)-directed MGDs for treating CCNE1-amplified solid tumors. Cyclin E1 is an oncogene commonly amplified in various cancers, yet the corresponding protein has historically been considered undruggable.

Monte Rosa's data reveals that their MGD can degrade Cyclin E1 with high selectivity, sparing other related proteins such as other cyclins and cyclin-dependent kinases (CDKs). This selective degradation leads to the inhibition of downstream pathways and suppresses tumor growth in models where CCNE1 is amplified and overexpressed. The company is continuing preclinical research to advance this program toward development candidate nomination.

Dr. Sharon Townson, Chief Scientific Officer at Monte Rosa Therapeutics, highlighted the significance of targeting Cyclin E1, a previously undruggable oncology target. She emphasized that Cyclin E1 MGDs represent a potentially groundbreaking precision medicine approach. The data indicate that these MGDs cause potent and selective degradation of Cyclin E1, which may reduce toxicities associated with inhibiting related cyclins and CDKs. This promising data supports continued preclinical development of Cyclin E1-directed MGDs as a new therapeutic option for various solid tumors including ovarian, endometrial, gastric, and breast cancers.

The poster titled "Selective Targeting of Cyclin E1 Using Molecular Glue Degraders in CCNE1 Amplified Solid Malignancies" (Poster Number 511) will be on display for the entire conference and presented daily by Ralph Tiedt, Vice President of Biology at Monte Rosa Therapeutics. Key findings include:

1. In cellular assays, MRT-50969 induced significant Cyclin E1 degradation, evidenced by the suppression of downstream pathways such as RB phosphorylation and E2F-driven gene expression.
2. MRT-50969 selectively inhibited proliferation and induced cell cycle arrest and senescence in CCNE1-amplified cancer cell lines, sparing those without amplification.
3. In preclinical models of CCNE1-amplified breast and gastric cancers, oral administration of MRT-50969 as a single agent resulted in robust tumor growth suppression and regression.
4. MRT-50969 showed higher selectivity compared to CDK2 inhibitors, inhibiting cell proliferation and downstream signaling in an RB-dependent manner.
5. Cryo-EM analysis revealed that Cyclin E1 can be engaged by cereblon-based MGDs through a previously undescribed binding mode, suggesting a larger target space for cereblon than previously known.

Cyclin E1 MGDs represent a novel therapeutic approach by targeting CCNE1-amplified malignancies, which are challenging to treat with conventional methods due to the non-enzymatic nature of the target. Preclinical studies demonstrated deep and selective target degradation, leading to significant tumor growth suppression and regression in in vivo models when dosed orally. This approach addresses high unmet medical needs in cancers such as ovarian, endometrial, gastric, and breast cancers.

Monte Rosa Therapeutics is a clinical-stage biotechnology company focused on developing highly selective MGDs for serious diseases in oncology, autoimmune, and inflammatory conditions. Their QuEEN™ discovery engine leverages AI-guided chemistry, diverse chemical libraries, structural biology, and proteomics to identify and design MGDs with unprecedented selectivity. Monte Rosa's pipeline spans various therapeutic areas and includes a strategic collaboration with Roche to develop MGDs against previously undruggable targets in cancer and neurological diseases.