Monte Rosa Therapeutics Presents Preclinical Data at American Association for Cancer Research (AACR) Annual Meeting 2025 on the Potential of its CDK2-directed Molecular Glue Degrader to Treat HR-positive/HER2-negative Breast Cancer
Monte Rosa Therapeutics (GLUE) presented preclinical data on MRT-51443, its CDK2-directed molecular glue degrader (MGD), for treating HR-positive/HER2-negative breast cancer at AACR 2025.
Key findings show that MRT-51443 in combination with CDK4/6 inhibition and anti-estrogen therapy achieved superior tumor regression compared to standard treatments. In the MCF7 model, the combination demonstrated -77% median tumor growth versus -3% for standard therapy. In the T47D model, it showed -61% versus -10%.
The drug exhibited potency, selectivity, and favorable drug-like properties, demonstrating superior selectivity compared to clinical-stage CDK2 inhibitors. MRT-51443 induced deep CDK2 degradation and delayed resistance to CDK4/6 inhibition. The company anticipates an IND submission for its cell cycle program in 2026.
Monte Rosa Therapeutics (GLUE) ha presentato dati preclinici su MRT-51443, il suo degrader molecolare (MGD) diretto contro CDK2, per il trattamento del tumore al seno HR-positivo/HER2-negativo durante l'AACR 2025.
I risultati principali mostrano che MRT-51443, in combinazione con l'inibizione di CDK4/6 e la terapia anti-estrogenica, ha ottenuto una regressione tumorale superiore rispetto ai trattamenti standard. Nel modello MCF7, la combinazione ha mostrato una crescita tumorale mediana del -77% contro il -3% della terapia standard. Nel modello T47D, ha evidenziato un -61% contro il -10%.
Il farmaco ha dimostrato potenza, selettività e proprietà farmacologiche favorevoli, con una selettività superiore rispetto agli inibitori di CDK2 in fase clinica. MRT-51443 ha indotto una profonda degradazione di CDK2 e ritardato la resistenza all'inibizione di CDK4/6. L'azienda prevede di presentare una richiesta IND per il suo programma sul ciclo cellulare nel 2026.
Monte Rosa Therapeutics (GLUE) presentó datos preclínicos sobre MRT-51443, su degradador molecular (MGD) dirigido a CDK2, para el tratamiento del cáncer de mama HR-positivo/HER2-negativo en AACR 2025.
Los hallazgos clave muestran que MRT-51443, en combinación con la inhibición de CDK4/6 y la terapia antiestrogénica, logró una regresión tumoral superior en comparación con los tratamientos estándar. En el modelo MCF7, la combinación mostró una disminución media del crecimiento tumoral del -77% frente al -3% del tratamiento estándar. En el modelo T47D, mostró un -61% frente a un -10%.
El fármaco exhibió potencia, selectividad y propiedades favorables similares a fármacos, demostrando una selectividad superior en comparación con los inhibidores de CDK2 en etapa clínica. MRT-51443 indujo una degradación profunda de CDK2 y retrasó la resistencia a la inhibición de CDK4/6. La compañía anticipa presentar una solicitud IND para su programa del ciclo celular en 2026.
Monte Rosa Therapeutics (GLUE)는 HR-양성/HER2-음성 유방암 치료를 위한 CDK2 표적 분자 글루 분해제(MGD)인 MRT-51443의 전임상 데이터를 AACR 2025에서 발표했습니다.
주요 결과에 따르면 MRT-51443은 CDK4/6 억제제 및 항에스트로겐 치료와 병용 시 표준 치료보다 우수한 종양 퇴축 효과를 보였습니다. MCF7 모델에서는 병용 요법이 표준 치료 대비 중앙 종양 성장률이 -77% 대 -3%를 나타냈으며, T47D 모델에서는 -61% 대 -10%를 기록했습니다.
이 약물은 강력한 효능, 선택성 및 우수한 약물 유사 특성을 보였으며, 임상 단계 CDK2 억제제보다 뛰어난 선택성을 입증했습니다. MRT-51443은 깊은 CDK2 분해를 유도하고 CDK4/6 억제제에 대한 내성을 지연시켰습니다. 회사는 2026년에 세포 주기 프로그램에 대한 IND 제출을 계획하고 있습니다.
Monte Rosa Therapeutics (GLUE) a présenté des données précliniques sur MRT-51443, son dégradeur moléculaire (MGD) ciblant CDK2, pour le traitement du cancer du sein HR-positif/HER2-négatif lors de l'AACR 2025.
Les résultats clés montrent que MRT-51443, en combinaison avec l'inhibition de CDK4/6 et une thérapie anti-œstrogène, a obtenu une régression tumorale supérieure par rapport aux traitements standards. Dans le modèle MCF7, la combinaison a montré une croissance tumorale médiane de -77 % contre -3 % pour la thérapie standard. Dans le modèle T47D, elle a atteint -61 % contre -10 %.
Le médicament a démontré puissance, sélectivité et propriétés favorables similaires à celles des médicaments, affichant une sélectivité supérieure aux inhibiteurs de CDK2 en phase clinique. MRT-51443 a induit une dégradation profonde de CDK2 et retardé la résistance à l'inhibition de CDK4/6. L'entreprise prévoit de soumettre une demande IND pour son programme sur le cycle cellulaire en 2026.
Monte Rosa Therapeutics (GLUE) stellte auf der AACR 2025 präklinische Daten zu MRT-51443 vor, einem molekularen Klebstoff-Degrader (MGD), der auf CDK2 abzielt, zur Behandlung von HR-positivem/HER2-negativem Brustkrebs.
Wesentliche Erkenntnisse zeigen, dass MRT-51443 in Kombination mit CDK4/6-Inhibition und Anti-Östrogen-Therapie eine überlegene Tumorrückbildung im Vergleich zu Standardbehandlungen erzielte. Im MCF7-Modell zeigte die Kombination ein medianes Tumorwachstum von -77 % gegenüber -3 % bei der Standardtherapie. Im T47D-Modell waren es -61 % gegenüber -10 %.
Das Medikament zeigte Wirksamkeit, Selektivität und günstige arzneimittelähnliche Eigenschaften und bewies eine überlegene Selektivität im Vergleich zu klinisch erprobten CDK2-Inhibitoren. MRT-51443 induzierte eine starke CDK2-Degradation und verzögerte die Resistenz gegen CDK4/6-Inhibition. Das Unternehmen plant die Einreichung eines IND für sein Zellzyklusprogramm im Jahr 2026.
- Superior tumor regression results: -77% vs -3% in MCF7 model
- Strong performance in T47D model: -61% vs -10% tumor growth
- Demonstrated superior selectivity compared to existing CDK2 inhibitors
- Successfully delayed resistance to CDK4/6 inhibition
- IND submission not planned until 2026
- Still in preclinical stage, requiring extensive clinical trials before potential approval
Insights
Monte Rosa's CDK2 degrader shows promising preclinical efficacy in breast cancer models, addressing resistance to standard therapy with 2026 IND planned.
Monte Rosa's latest preclinical data for their CDK2-directed molecular glue degrader (MRT-51443) represents a notable development in their pipeline. The compound shows impressive tumor regression when combined with current standard-of-care therapies in HR+/HER2- breast cancer models. The combination achieved
The strategic targeting of CDK2 is particularly promising as CDK2 activation represents a known resistance mechanism to CDK4/6 inhibitors, which are currently the backbone of HR+/HER2- breast cancer treatment. This approach directly addresses a major limitation of current therapies. The molecular glue degrader platform potentially offers superior selectivity compared to traditional inhibitors, which could translate to better tolerability if confirmed in clinical studies.
While these results are encouraging, the developmental timeline places an IND submission in 2026, meaning that any potential commercialization remains several years away. The HR+/HER2- breast cancer market represents approximately
Preclinical data shows Monte Rosa's CDK2 degrader dramatically enhanced tumor regression in breast cancer models compared to standard therapy, addressing a critical resistance mechanism.
The preclinical results for MRT-51443 demonstrate particularly promising efficacy in addressing a critical unmet need in HR+/HER2- breast cancer treatment. The magnitude of tumor response is noteworthy - when combined with ribociclib and fulvestrant, MRT-51443 achieved -77% tumor growth versus just -3% for standard therapy in the MCF7 model, and -61% versus -10% in the T47D model. These are substantial improvements over current standard-of-care approaches.
CDK2 activation represents a primary escape mechanism when tumors develop resistance to CDK4/6 inhibition, which inevitably occurs in most patients. By specifically degrading CDK2 rather than inhibiting it, MRT-51443 takes a mechanistically distinct approach that could overcome limitations of CDK2 inhibitors currently in clinical development. The data showing delayed resistance to CDK4/6 inhibition in vitro supports this mechanistic rationale.
The superior selectivity versus clinical-stage CDK2 inhibitors is particularly important in this patient population, as HR+/HER2- breast cancer patients often require long-term treatment. Improved selectivity could potentially translate to better tolerability, which is critical for maintenance therapy scenarios. While these preclinical results are encouraging, the translation to human studies will be key, with IND filing anticipated in 2026. The triple combination approach aligns with the clinical treatment paradigm, potentially facilitating eventual clinical adoption if the efficacy and safety profiles are confirmed in human studies.
CDK2 molecular glue degrader (MGD) in combination with CDK4/6 inhibition and anti-estrogen therapy achieved superior tumor regression in vivo compared to standard of care CDK4/6 inhibition and anti-estrogen therapy
CDK2 MGD delayed resistance to CDK4/6 inhibition in vitro and displayed superior selectivity versus clinical-stage CDK2 inhibitors
BOSTON, April 28, 2025 (GLOBE NEWSWIRE) -- 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 on the potential of its highly selective cyclin-dependent kinase 2 (CDK2)-directed molecular glue degrader, MRT-51443, to treat HR-positive/HER2-negative breast cancer at the American Association for Cancer Research (AACR) Annual Meeting 2025, being held April 25-30 in Chicago, IL.
“In preclinical models of HR-positive/HER2-negative breast cancer, the combination of MRT-51443 with a CDK4/6 inhibitor and anti-estrogen therapy drove robust tumor regressions, demonstrating notably deeper tumor responses than the standard of care combination alone,” said Sharon Townson, Ph.D., Chief Scientific Officer of Monte Rosa Therapeutics. “These results suggest that our highly selective, oral CDK2 degrader MRT-51443 has the potential to improve on current standard of care therapy for HR-positive/HER2-negative breast cancer. In addition, we believe our MGD approach could avoid many of the toxicities associated with less selective CDK2 inhibitors, which is critically important for a potentially differentiated therapy in this patient population. The degree to which CDK2 degradation with MRT-51443 delayed resistance to CDK4/6 inhibition in vitro was also striking, as patients treated with CDK4/6 inhibitors often relapse because their tumors become reliant on the CDK2 pathway. We anticipate an IND submission for our cell cycle program in 2026.”
The poster, entitled, “Selective Targeting of CDK2 Using Molecular Glue Degraders for the Treatment of HR-Positive/HER2-Negative Breast Cancer” (Poster Number LB422), will be displayed on April 30, 2025, from 9am to 12pm CST in Poster Section 51, Poster Board 4. The poster will be presented by Sofia Gkountela, Associate Director, Biology, and Nina Ilic-Widlund, Director, Biology, Monte Rosa Therapeutics.
Summary of findings:
- MRT-51443 exhibited potency, selectivity, and favorable drug-like properties.
- MRT-51443 demonstrated superior selectivity as compared to several clinical-stage small molecule CDK2 inhibitors.
- In cellular assays, MRT-51443 induced deep CDK2 degradation, resulting in CDK2-dependent cancer cell growth inhibition.
- Degradation of CDK2 with MRT-51443 delayed resistance to CDK4/6 inhibition in vitro and exhibited strong anti-tumor activity in combination with CDK4/6 inhibitors in vivo.
- MRT-51443 in combination with CDK4/6 inhibition and anti-estrogen therapy drove deep tumor regressions and achieved superior tumor regression compared to standard of care CDK4/6 inhibition and anti-estrogen therapy in HR+/HER2- breast cancer models.
- Specifically, in the MCF7 model, the combination of MRT-51443 + ribociclib + fulvestrant demonstrated median tumor growth of -
77% versus -3% for ribociclib + fulvestrant. In the T47D model, MRT-51443 + ribociclib + fulvestrant demonstrated median tumor growth of -61% versus -10% for ribociclib + fulvestrant. The combination of MRT-51443 + ribociclib also resulted in robust tumor regression in both models.
About CDK2 MGDs and MRT-51443
Cyclin-dependent kinase 2 (CDK2) is a key driver of cell cycle progression in cancer, acting in coordination with CDK4 and CDK6 to drive cell proliferation. CDK4/6 inhibitors, in combination with endocrine therapy, are FDA-approved agents for the treatment of HR-positive/HER2-negative breast cancer; however, many patients become resistant because their tumors become reliant on CDK2. Targeting CDK2 in conjunction with CDK4/6 inhibition has the potential to provide more sustained clinical responses. In preclinical studies, Monte Rosa’s next-generation CDK2-targeted MGD, MRT-51443, has demonstrated highly selective degradation of CDK2, with no detectable off-target activity. MRT-51443 induced robust downstream CDK2 pathway suppression and drove deep tumor regression, achieving greater anti-tumor activity than current standard of care therapeutics, in preclinical models of HR-positive/HER2-negative breast cancer when combined with either a CDK4/6 inhibitor or a CDK4/6 inhibitor plus an anti-estrogen therapy. Targeting CDK2 with MRT-51443 represents a potentially novel approach to treating HR-positive/HER2-negative breast cancer in combination with current standard of care therapies.
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. Monte Rosa has a global license agreement with Novartis to advance VAV1-directed molecular glue degraders and 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.
Forward-Looking Statements
This communication includes express and implied “forward-looking statements,” including forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include all statements that are not historical facts and in some cases, can be identified by terms such as “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “intend,” “plan,” “objective,” “anticipate,” “believe,” “estimate,” “predict,” “potential,” “continue,” “ongoing,” or the negative of these terms, or other comparable terminology intended to identify statements about the future. Forward-looking statements contained herein include, but are not limited to, statements about the therapeutic potential of CDK2 degradation, including using the company’s CDK2-directed MGDs, including MRT-51443, that degrading CDK2 in conjunction with CDK4/6 inhibition and hormone therapy has the potential to provide more sustained responses in patients with HR-positive/HER2-negative breast cancer than current standard of care therapy including CDK4/6 inhibition and hormone therapy, about preclinical data presented at the American Association for Cancer Research (AACR) Annual Meeting 2025 supporting the potential of its highly selective cyclin dependent kinase 2 (CDK2)-directed molecular glue degrader to treat HR-positive/HER2-negative breast cancer, and about the Potential of CDK2-directed MGDs, including MRT-51443, to provide more sustained responses in a difficult-to-treat patient population while avoiding toxicities typically associated with limited selectivity of CDK2 inhibitors, among others. By their nature, these statements are subject to numerous risks and uncertainties, including those risks and uncertainties set forth in our most recent Annual Report on Form 10-K for the year ended December 31, 2024, filed with the U.S. Securities and Exchange Commission on March 20, 2025, and any subsequent filings, that could cause actual results, performance or achievement to differ materially and adversely from those anticipated or implied in the statements. You should not rely upon forward-looking statements as predictions of future events. Although our management believes that the expectations reflected in our statements are reasonable, we cannot guarantee that the future results, performance, or events and circumstances described in the forward-looking statements will be achieved or occur. Recipients are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date such statements are made and should not be construed as statements of fact. We undertake no obligation to publicly update any forward-looking statements, whether as a result of new information, any future presentations, or otherwise, except as required by applicable law. Certain information contained in these materials and any statements made orally during any presentation of these materials that relate to the materials or are based on studies, publications, surveys and other data obtained from third-party sources and our own internal estimates and research. While we believe these third-party studies, publications, surveys and other data to be reliable as of the date of these materials, we have not independently verified, and make no representations as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, no independent source has evaluated the reasonableness or accuracy of our internal estimates or research and no reliance should be made on any information or statements made in these materials relating to or based on such internal estimates and research.
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FAQ
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