MRT-2359 / Monte Rosa Therap - LARVOL DELTA

Monte Rosa Therapeutics Announces First Patient Dosed in MODeFIRe-1, a Phase 2 Study of MRT-2359 in Combination with Apalutamide in Patients with AR Mutation-Positive Metastatic Castration-Resistant Prostate Cancer (GlobeNewswire) - "MODeFIRe-1 will evaluate MRT-2359 at a dose of 0.5 mg administered orally on a 21 days on, 7 days off schedule over 28-day cycles, in combination with apalutamide. The study will enroll up to 25 patients with mCRPC with AR mutations, utilizing a Simon’s two-stage design."

Trial status • Castration-Resistant Prostate Cancer

Enrollment in the initial Phase 1/2 study expansion arm in patients with advanced CRPC has been completed (GlobeNewswire) - "A total of 6 patients with AR mutations were enrolled and treated with MRT-2359 in combination with enzalutamide. Monte Rosa plans to provide an update on this patient subset by the end of the year."

Enrollment status • P1/2 data • Castration-Resistant Prostate Cancer

Elucidating the mechanism of ENaC activity reduction by molecular glue degrader drugs (NACFC 2026) - "Previous work has shown that the GSPT1/eRF3a-degrading MGDs CC-90009, SJ6986, and MRT-2359 reduce ENaC activity, but the seven additional MGDs used here did not at the doses tested. [1,3] CC-90009 reduces ENaC activity in a cereblon-dependent and GSPT1/eRF3a-independent fashion, suggesting that this mechanism leverages the cereblon-based ubiquitination and degradation of a neosubstrate involved in ENaC activity or regulation. Though we knocked down putative neosubstrates, this pathway remains unelucidated."

Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • AVEN • CRBN • GSPT1

MODeFIRe-1: Study of Oral MRT-2359 With Apalutamide in Prostate Cancer (clinicaltrials.gov) - P2 | N=25 | Recruiting | Sponsor: Monte Rosa Therapeutics, Inc

New P2 trial • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • AR

Development of XYD113 as a potent and highly selective GSPT1 degrader for cancer therapy. (PubMed, Acta Pharmacol Sin) - "In vivo, oral administration of XYD113 (5 mg/kg, daily for 21 days) significantly inhibited 22Rv1 xenograft growth (TGI = 46%) and showed a favorable safety profile in BALB/c-nude mice. Together, these findings highlight XYD113 as a promising therapeutic degrader worthy of further development for the treatment of MYC-driven cancers."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • CRBN • GSPT1 • IKZF1 • MYC • SALL4

Proteome-wide target engagement and ternary complex mapping of molecular glues using LiP-MS (AACR 2026) - "This live-cell format enables detection of secondary, compound-dependent protein recruitment events, including ternary complex formation with E3 ligases and other associated proteins.To evaluate LiP-MS performance in characterizing molecular glue mechanisms, we conducted global target identification experiments using two representative compounds: SR-4835, a cyclin K degrader that binds CDK12 and recruits DDB1, and MRT-2359, a GSPT1 degrader that engages CRBN. Live-cell LiP-MS experiments were performed at two time points (1 hour and 6 hours) to monitor compound-dependent conformational changes and protein recruitment dynamics associated with primary target engagement and potential ternary complex formation.Together, LiP-MS provides a comprehensive, high-resolution platform for mapping small-molecule target engagement and for characterizing dynamic protein recruitment events associated with molecular glue activity directly in the cellular environment."

Oncology • CDK12 • CRBN • DDB1 • GSPT1

Seeking new glues - Toward an E3 ligase-agnostic molecular glue degrader identification platform (AACR 2025) - "Conversely, a key challenge with cell-based screening approaches is to understand the mechanism by which the target is degraded, relying on the identification of the ubiquitin ligase or adaptor protein that is mediating the effect of the compound.Here, we demonstrate the utility of our cell-based screening platform by developing degrader assays for two separate targets, Cyclin K and GSPT1, both therapeutically relevant for oncology, and with respective MGDs in clinical trials (CT7439 for cyclin K by Carrick Therapeutics, and MRT-2359 and Eragidomide from Monte Rosa Therapeutics and Cellgene/BMS, respectively).Further, to address the challenge of deconvoluting the mechanistic basis for monovalent degrader hits from cell-based assays, we have utilized limited proteolysis coupled with mass spectrometry (LiP-MS)...This methodology allows the identification of the proteins involved in mediating degradation of a target, such as a ubiquitin ligase recruited to a target via an..."

Oncology • GSPT1

The GSPT1 molecular glue degrader MRT-2359 is active against prostate cancer (AACR 2024) - P1/2 | "No significant in vivo response was observed for xenografts of the insensitive cell line PC-3. These data support the clinical investigation of MRT-2359 in prostate cancer."

Genito-urinary Cancer • Genitourinary Neuroendocrine Carcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • AR • GSPT1 • MYC • MYCN

Drug target ID and binding site mapping in complex cellular environments using LiP-MS (AACR 2025) - "This workflow bypasses the need for protein purification, mitigating risks of protein truncation or misfolding.To evaluate LiP-MS' performance on molecular glue MoAs, we performed global target ID experiments using two well-characterized models: the cyclin K degraders CR8 and SR-4835 and the GSPT1 degraders MRT-2359 and Eragidomide...Applying HR-LiP, we mapped the binding site of the BRD4 inhibitor JQ1 on full-length BRD4, a large protein challenging to study via standard methods, using a mammalian transient overexpression system. Similarly, we located binding sites for EGFR inhibitors gefitinib and afatinib on the membrane-bound EGFR protein. Additionally, we pinpointed the SMER28 binding site on the hexameric ATPase VCP, an autophagy enhancer, demonstrating the method's applicability to large protein complexes.In conclusion, LiP-MS provides a versatile toolbox for identifying drug targets and mapping binding sites within complex cellular environments."

Oncology • BRD4 • CDK12 • CRBN • DDB1 • GSPT1

Discovery of novel, potent and orally active GSPT1 molecular glue degraders (AACR 2025) - "In fact, clinical proof of concept has been obtained with immunomodulatory drugs such as thalidomide, lenalidomide and pomalidomide, which degrade IKZF1/IKZF3...GSPT1 degrader antibody conjugates are now in clinical trials for breast cancer (ORM-5029) and AML (BMS-986497/ORM-6151)...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...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."

Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BCL6 • GSPT1 • IKZF1 • IKZF3 • STAT6 • VAV1

Monte Rosa Therapeutics…announced the company has entered into a supply agreement with Johnson & Johnson to evaluate MRT-2359 in combination with ERLEADA (apalutamide) for the treatment of patients with…mCRPC with androgen receptor (AR) mutations in a planned Phase 2 study expected to initiate in the third quarter of 2026 (GlobeNewswire) - "The planned Phase 2 study of up to 25 mCRPC patients is designed to efficiently assess the efficacy and safety of MRT-2359 plus ERLEADA in mCRPC patients with AR mutations, with potential to expand the study into additional patient subsets, including patients naïve to next-generation AR inhibitors, should the activity in the AR mutant patient population confirm."

Commercial • New P2 trial • Castration-Resistant Prostate Cancer

A phase 1/2 study of MRT-2359, a highly selective oral GSPT1 molecular glue degrader (MGD), in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) harboring AR ligand binding domain (LBD) mutations. (ASCO-GU 2026) - P1/2 | "Preliminary signals of anticancer activity have been observed, including in all 3 patients with AR LBD mutations, who demonstrated 2 (67%) partial responses (PRs; -62% tumor reduction maintained for 10 cycles in a patient with ARH875Ypost NHA, docetaxel and lutetium-177 PSMA; -61% ongoing for 3+ cycles in a patient with ARH875Y post NHA including enzalutamide, docetaxel and lutetium-177 PSMA ) and 1 durable stable disease (SD; -20% ongoing for 8+ cycles in a patient with ARL702H post NHA including enzalutamide, docetaxel and PSMA T-cell engager)... MRT-2359, an orally bioavailable, highly selective GSPT1 MGD was safe with encouraging preliminary activity (PR rate 67%, ≥ PSA50 rate 100%) in mCRPC with AR LBD mutations."

Combination therapy • Metastases • P1/2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CCND1 • GSPT1

MRT-2359-001: Study of Oral MRT-2359 in Selected Cancer Patients (clinicaltrials.gov) - P1/2 | N=174 | Active, not recruiting | Sponsor: Monte Rosa Therapeutics, Inc | Recruiting ➔ Active, not recruiting

Enrollment closed • B Cell Lymphoma • Breast Cancer • Diffuse Large B Cell Lymphoma • Endocrine Cancer • Genito-urinary Cancer • Hematological Malignancies • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • HER-2 • MYC • MYCN

Monte Rosa Therapeutics Presents Updated Clinical Data from Phase 1/2 Study of MRT-2359 in Combination with Enzalutamide in Heavily Pretreated Metastatic Castration-Resistant Prostate Cancer Patients at ASCO Genitourinary Cancers Symposium (ASCO GU) (GlobeNewswire) - "In mCRPC patients with androgen receptor (AR) mutations, treatment with MRT-2359 in combination with enzalutamide led to a 100% PSA response rate (5 of 5 patients) and a 100% disease control rate, including 2 patients with RECIST partial responses and 3 with stable disease, all showing reduction in size of target lesions. Across all 15 evaluable patients, the overall RECIST disease control rate was 67%, and 10 of 15 patients showed tumor size reductions of target lesions."

P1/2 data • Castration-Resistant Prostate Cancer

Monte Rosa plans to initiate a Phase 2 study of MRT-2359 in combination with a second-generation AR inhibitor (GlobeNewswire) - "The study of up to 25 mCRPC patients, utilizing a two-stage design, is designed to efficiently assess the efficacy of MRT-2359 plus a second-generation AR inhibitor in mCRPC patients with AR mutations, with potential to expand the study into additional patient subsets, including patients naive to second-generation AR inhibitors. The study, anticipated to start in Q3 2026, will evaluate PSA response, RECIST response, duration of response, radiographic progression-free survival (rPFS), and safety."

New P2 trial • Castration-Resistant Prostate Cancer

Company plans to initiate a new, signal-confirming Phase 2 study of MRT-2359 targeting AR mutant and AR signaling-dependent patients in 2026 (GlobeNewswire) - "The study of up to 25 mCRPC patients, utilizing a two-stage design, is designed to efficiently assess the efficacy of MRT-2359 plus an AR inhibitor in mCRPC patients with AR mutations, with potential to expand the study into additional patient subsets, including patients naïve to 2nd generation AR inhibitors, should the activity in the AR mutant patient population confirm."

New P2 trial • Castration-Resistant Prostate Cancer

Monte Rosa Therapeutics Announces Compelling Clinical Activity of MRT-2359 in Combination with Enzalutamide in Heavily Pretreated Metastatic Castration-Resistant Prostate Cancer Patients with Androgen Receptor Mutations (GlobeNewswire) - "In mCRPC patients with androgen receptor (AR) mutations, treatment with MRT-2359 in combination with enzalutamide led to a 100% PSA response rate (4 of 4 patients) and a 100% disease control rate, including 2 patients with RECIST responses and 2 with stable disease; Combination of MRT-2359 and enzalutamide was generally well-tolerated with primarily Grade 1-2 adverse events....Updated MRT-2359 data expected to be presented at ASCO Genitourinary Cancers Symposium in February 2026."

P1/2 data • Castration-Resistant Prostate Cancer

Monte Rosa Therapeutics…announced that management will host a live conference call and webcast on Tuesday, December 16, 2025, at 8:00 a.m. ET (GlobeNewswire) - "The webcast presentation will highlight interim clinical results from the ongoing Phase 1/2 study of the GSPT1-directed MGD MRT-2359 in heavily pretreated, metastatic castration-resistant prostate cancer (mCRPC) patients."

P1/2 data • Castration-Resistant Prostate Cancer

The dual-target molecular glue degrader INNO-235 effectively mediates the degradation of GSPT1 and CK1α, and exhibits potent anti-tumor activity in TP53 mutant burkitt lymphoma (ASH 2025) - "Notably,compared to INNO-220 (a CK1α single-target molecular glue degrader) and MRT-2359 (a GSPT1 single-target molecular glue degrader), INNO-235 demonstrated superior anti-tumor activity and overallsurvival.To elucidate INNO-235's mechanism of action, we performed RNA-seq analysis in INNO-235 treatedDaudi cells...These findingsindicated that INNO-235 induced p53-independent apoptosis in TP53-mutated BL cells through ISRpathway activation.In conclusion, INNO-235 represents a first-in-class GSPT1/CK1α dual-target molecular glue degrader withsignificant therapeutic potential for lymphomas. By inducing both p53-dependent and TP53-independentapoptosis, INNO-235 offers a promising therapeutic strategy for TP53-mutated BL and other MYC-drivenmalignancies with limited treatment options."

IO biomarker • Burkitt Lymphoma • CNS Disorders • Hematological Malignancies • Lymphoma • Oncology • Targeted Protein Degradation • ATF4 • BCL2 • CRBN • GSPT1 • IKZF1 • IKZF3 • MYC • TP53

MRT-2359 - a novel molecular glue degrader of eRF3a induces readthrough of CFTR PTC variants (NACFC 2025) - "When combined with AGs G418 or ELX-02, MRT-2359 exhibited synergistic effects that further promoted functional readthrough in G542X, R1162X, and W1282X models, outperforming CC-90009... MRT-2359, alone or in combination with readthrough-promoting AGs, partially restores CFTR function for multiple CFTR PTC variants. These findings support further explorations of eRF3a as a therapeutic target for treating CF caused by nonsense variants."

Cystic Fibrosis • Genetic Disorders • Genito-urinary Cancer • Immunology • Prostate Cancer • Respiratory Diseases • Solid Tumor • Targeted Protein Degradation • CFTR • GSPT1

Monte Rosa Therapeutics Announces First Quarter 2025 Financial Results and Business Updates (GlobeNewswire) - "Share additional MRT-2359 Phase 1/2 study data in CRPC patients resistant to androgen receptor (AR) therapy and in patients with HR+ breast cancer in H2 2025....Submit an IND application for a CDK2 and/or cyclin E1-directed MGD in 2026."

IND • P1/2 data • Castration-Resistant Prostate Cancer • Hormone Receptor Positive Breast Cancer • Solid Tumor

Monte Rosa Therapeutics Announces First Quarter 2025 Financial Results and Business Updates (GlobeNewswire) - "Research and Development (R&D) Expenses: R&D expenses for the first quarter of 2025 were $32.2 million, compared to $27.0 million for the first quarter of 2024. These increases were driven by the successful achievement of key milestones in our R&D organization, including the continuation of the MRT-2359 clinical study, the progression and growth of our preclinical pipeline, including research performed in connection with our collaboration with Roche, the advancement of MRT-6160 to enter the clinic..."

Commercial • Castration-Resistant Prostate Cancer • HER2 Positive Breast Cancer • Immunology • Solid Tumor

MRT-2359, GSPT1-directed MGD for MYC-driven solid tumors (GlobeNewswire) - P1/2 | N=174 | NCT05546268 | Sponsor: Monte Rosa Therapeutics, Inc | "Using the 5/9 dosing schedule, doses of 0.5 mg and 1 mg per day were generally well tolerated with mostly low-grade adverse events (AEs)...Using the 21/7 schedule, both the 0.5 and 0.75 mg doses were generally well tolerated with mostly low-grade AEs observed. The 0.5 mg dose using the 21/7 dose schedule was selected as the recommended phase 2 dose (RP2D). Optimal degradation (based on optimal PD modulation in preclinical studies) of approximately 60% was achieved in biomarker L-/N-MYC high tumor samples, as assessed by targeted mass spectrometry... there was 1 confirmed partial response (PR), and 4 patients with stable disease (SD), for a disease control rate (DCR) of 38%. Of 24 biomarker negative patients (low L-MYC and N-MYC expression), there was 1 unconfirmed PR and 3 patients with SD, for a DCR of 17%...expects to present additional results for this cohort in H2 2025."

P1/2 data • Non Small Cell Lung Cancer • Small Cell Lung Cancer

Monte Rosa Therapeutics Announces Fourth Quarter 2024 Financial Results and Provides Corporate… (GlobeNewswire) - "Submit an IND application for MRT-8102 in H1 2025. Submit an IND application for the second generation NEK7-directed MGD with enhanced CNS penetration in 2026."

IND • Immunology • Inflammation • Oncology

Monte Rosa Therapeutics to Present Pipeline Update and Release Fourth Quarter and Full Year 2024 Financial Results on March 20, 2025 (GlobeNewswire) - "Monte Rosa Therapeutics, Inc...announced that management will present a pipeline update including clinical results from its Phase 1 SAD/MAD study of the VAV1-directed MGD MRT-6160 and its Phase 1/2 study of MRT-2359 in MYC-driven solid tumors. A conference call and webcast are planned for Thursday, March 20, 2025, at 8:00 a.m. ET."

P1 data • P1/2 data • HER2 Negative Breast Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Prostate Cancer • Small Cell Lung Cancer