Cyclin E1 molecular glue degraders (MGDs) represent a potential novel therapeutic approach by directly and selectively targeting a frequently amplified non-enzymatic driver oncogene relevant in multiple solid tumors
Cyclin E1 MGD inhibited tumor growth in CCNE1-amplified cancer models in vivo
BOSTON, MA, USA I October 23, 2024 I Monte Rosa Therapeutics, Inc. (Nasdaq: GLUE), a clinical-stage biotechnology company developing novel molecular glue degrader (MGD)-based medicines, today announced the company will present preclinical data at the 36th EORTC-NCI-AACR Symposium (ENA 2024), taking place in Barcelona, Spain from October 23 to 25, on the potential of its cyclin E1 (CCNE1)-directed molecular glue degraders (MGDs) for the treatment of CCNE1-amplified solid tumors. CCNE1 is a well-validated oncogene that is amplified in multiple tumor types, but the corresponding cyclin E1 protein has traditionally been undruggable. The data being presented demonstrate that Monte Rosa’s MGD degrades cyclin E1 with a high level of selectivity, sparing other closely related proteins, including other cyclins, and cyclin-dependent kinases (CDKs). The data also showed that a cyclin E1-directed MGD led to downstream pathway inhibition and induced tumor growth suppression and regression preferentially in CCNE1-amplified and over-expressing tumor cell lines and xenograft models. The Company continues to perform preclinical research in order to progress the program towards a development candidate nomination.
“Cyclin E1 (CCNE1) has long been a high interest yet undruggable oncology target. By directly and selectively targeting this frequently amplified non-enzymatic driver oncogene, cyclin E1 MGDs represent a potential paradigm shift and novel precision medicine approach,” said Sharon Townson, Ph.D., Chief Scientific Officer of Monte Rosa Therapeutics. “Our results demonstrate that our cyclin E1-targeted MGD drives highly selective and potent degradation of cyclin E1, which we believe is important because it could reduce toxicities associated with inhibition of closely related cyclins as well as CDKs. We believe these promising data support continued preclinical development and the potential of cyclin E1-directed MGDs as an important new therapeutic approach for various solid tumors, including ovarian, endometrial, gastric, breast, and other cancers.”
The poster, entitled, “Selective Targeting of Cyclin E1 Using Molecular Glue Degraders in CCNE1 Amplified Solid Malignancies” (Poster Number 511), will be displayed for the duration of the conference in the Late Breaking Posters section and presented each day during the lunchtime period by Ralph Tiedt, Vice President, Biology, Monte Rosa Therapeutics.
Summary of findings:
- In cellular assays, MRT-50969 induced deep cyclin E1 degradation in conjunction with downstream pathway suppression, as evidenced by downmodulation of RB phosphorylation and E2F-driven gene expression.
- MRT-50969 selectively inhibited proliferation and induced G1-S cell cycle arrest and senescence in CCNE1-amplified cancer cell lines, while sparing cell lines without amplification.
- When dosed orally as a single agent in preclinical models of CCNE1-amplified breast cancer and gastric cancer, the cyclin E1-directed MGD MRT-50969 induced robust tumor growth suppression and regression.
- Unlike CDK2 inhibitors, MRT-50969 inhibited cell proliferation and downstream signaling in an RB-dependent manner, attesting to its higher level of selectivity compared to leading CDK2 inhibitors.
- Cryo-EM analysis showed that cyclin E1 can be engaged by cereblon-based MGDs through a cryptic pocket on the cyclin E1 surface, revealing a previously undescribed binding mode and suggesting that the target space for cereblon is larger than previously thought.
About Cyclin E1 (CCNE1) MGDs
Cyclin E1 (CCNE1) is a critical driver of cell cycle progression and cell proliferation that is frequently amplified or overexpressed in solid malignancies including ovarian, endometrial, gastric, breast, and other cancers. CCNE1 amplification is associated with poor patient survival. This target has previously been considered undruggable with conventional approaches due to lack of enzymatic activity. In preclinical studies, cyclin E1-targeted MGDs have resulted in deep and highly selective target degradation. When dosed orally as a single agent in CCNE1-amplified in vivo models, cyclin E1-targeted MGDs induced robust tumor growth suppression and regression. Targeting cyclin E1 with a MGD represents a potentially novel approach to target multiple CCNE1-amplified solid malignancies with high unmet medical need, including ovarian, endometrial, gastric, breast and others.
About Monte Rosa
Monte Rosa Therapeutics is a clinical-stage biotechnology company developing highly selective molecular glue degrader (MGD) medicines for patients living with serious diseases in the areas of oncology, autoimmune and inflammatory diseases, and more. MGDs are small molecule protein degraders that have the potential to treat many diseases that other modalities, including other degraders, cannot. Monte Rosa’s QuEEN™ (Quantitative and Engineered Elimination of Neosubstrates) discovery engine combines AI-guided chemistry, diverse chemical libraries, structural biology and proteomics to identify degradable protein targets and rationally design MGDs with unprecedented selectivity. The QuEEN discovery engine enables access to a wide-ranging and differentiated target space of well-validated biology across multiple therapeutic areas. Monte Rosa has developed the industry’s leading pipeline of MGDs, which spans oncology, autoimmune and inflammatory disease and beyond, and has a strategic collaboration with Roche to discover and develop MGDs against targets in cancer and neurological diseases previously considered impossible to drug. For more information, visit www.monterosatx.com.
SOURCE: Monte Rosa Therapeutics
Post Views: 146
Cyclin E1 molecular glue degraders (MGDs) represent a potential novel therapeutic approach by directly and selectively targeting a frequently amplified non-enzymatic driver oncogene relevant in multiple solid tumors
Cyclin E1 MGD inhibited tumor growth in CCNE1-amplified cancer models in vivo
BOSTON, MA, USA I October 23, 2024 I Monte Rosa Therapeutics, Inc. (Nasdaq: GLUE), a clinical-stage biotechnology company developing novel molecular glue degrader (MGD)-based medicines, today announced the company will present preclinical data at the 36th EORTC-NCI-AACR Symposium (ENA 2024), taking place in Barcelona, Spain from October 23 to 25, on the potential of its cyclin E1 (CCNE1)-directed molecular glue degraders (MGDs) for the treatment of CCNE1-amplified solid tumors. CCNE1 is a well-validated oncogene that is amplified in multiple tumor types, but the corresponding cyclin E1 protein has traditionally been undruggable. The data being presented demonstrate that Monte Rosa’s MGD degrades cyclin E1 with a high level of selectivity, sparing other closely related proteins, including other cyclins, and cyclin-dependent kinases (CDKs). The data also showed that a cyclin E1-directed MGD led to downstream pathway inhibition and induced tumor growth suppression and regression preferentially in CCNE1-amplified and over-expressing tumor cell lines and xenograft models. The Company continues to perform preclinical research in order to progress the program towards a development candidate nomination.
“Cyclin E1 (CCNE1) has long been a high interest yet undruggable oncology target. By directly and selectively targeting this frequently amplified non-enzymatic driver oncogene, cyclin E1 MGDs represent a potential paradigm shift and novel precision medicine approach,” said Sharon Townson, Ph.D., Chief Scientific Officer of Monte Rosa Therapeutics. “Our results demonstrate that our cyclin E1-targeted MGD drives highly selective and potent degradation of cyclin E1, which we believe is important because it could reduce toxicities associated with inhibition of closely related cyclins as well as CDKs. We believe these promising data support continued preclinical development and the potential of cyclin E1-directed MGDs as an important new therapeutic approach for various solid tumors, including ovarian, endometrial, gastric, breast, and other cancers.”
The poster, entitled, “Selective Targeting of Cyclin E1 Using Molecular Glue Degraders in CCNE1 Amplified Solid Malignancies” (Poster Number 511), will be displayed for the duration of the conference in the Late Breaking Posters section and presented each day during the lunchtime period by Ralph Tiedt, Vice President, Biology, Monte Rosa Therapeutics.
Summary of findings:
- In cellular assays, MRT-50969 induced deep cyclin E1 degradation in conjunction with downstream pathway suppression, as evidenced by downmodulation of RB phosphorylation and E2F-driven gene expression.
- MRT-50969 selectively inhibited proliferation and induced G1-S cell cycle arrest and senescence in CCNE1-amplified cancer cell lines, while sparing cell lines without amplification.
- When dosed orally as a single agent in preclinical models of CCNE1-amplified breast cancer and gastric cancer, the cyclin E1-directed MGD MRT-50969 induced robust tumor growth suppression and regression.
- Unlike CDK2 inhibitors, MRT-50969 inhibited cell proliferation and downstream signaling in an RB-dependent manner, attesting to its higher level of selectivity compared to leading CDK2 inhibitors.
- Cryo-EM analysis showed that cyclin E1 can be engaged by cereblon-based MGDs through a cryptic pocket on the cyclin E1 surface, revealing a previously undescribed binding mode and suggesting that the target space for cereblon is larger than previously thought.
About Cyclin E1 (CCNE1) MGDs
Cyclin E1 (CCNE1) is a critical driver of cell cycle progression and cell proliferation that is frequently amplified or overexpressed in solid malignancies including ovarian, endometrial, gastric, breast, and other cancers. CCNE1 amplification is associated with poor patient survival. This target has previously been considered undruggable with conventional approaches due to lack of enzymatic activity. In preclinical studies, cyclin E1-targeted MGDs have resulted in deep and highly selective target degradation. When dosed orally as a single agent in CCNE1-amplified in vivo models, cyclin E1-targeted MGDs induced robust tumor growth suppression and regression. Targeting cyclin E1 with a MGD represents a potentially novel approach to target multiple CCNE1-amplified solid malignancies with high unmet medical need, including ovarian, endometrial, gastric, breast and others.
About Monte Rosa
Monte Rosa Therapeutics is a clinical-stage biotechnology company developing highly selective molecular glue degrader (MGD) medicines for patients living with serious diseases in the areas of oncology, autoimmune and inflammatory diseases, and more. MGDs are small molecule protein degraders that have the potential to treat many diseases that other modalities, including other degraders, cannot. Monte Rosa’s QuEEN™ (Quantitative and Engineered Elimination of Neosubstrates) discovery engine combines AI-guided chemistry, diverse chemical libraries, structural biology and proteomics to identify degradable protein targets and rationally design MGDs with unprecedented selectivity. The QuEEN discovery engine enables access to a wide-ranging and differentiated target space of well-validated biology across multiple therapeutic areas. Monte Rosa has developed the industry’s leading pipeline of MGDs, which spans oncology, autoimmune and inflammatory disease and beyond, and has a strategic collaboration with Roche to discover and develop MGDs against targets in cancer and neurological diseases previously considered impossible to drug. For more information, visit www.monterosatx.com.
SOURCE: Monte Rosa Therapeutics
Post Views: 146
