SGR-4174 / Schrodinger - LARVOL DELTA

Preclinical characterization of SGR-4174, a potent and selective SOS1 inhibitor for the treatment of pan KRAS mutant cancers in combination with KRAS pathway inhibitors (AACR 2025) - "Compared to other published SOS1 inhibitors (BI-3406, MRTX0902), SGR-4174 is more potent, and demonstrated similar anti-tumor activity and target engagement at a lower dose both in monotherapy and combination therapy studies in xenograft tumor models. SGR-4174 was well tolerated as monotherapy and in combination with sotorasib or trametinib.SGR-4174 demonstrated favorable PK properties across preclinical species and toxicity profile was well characterized. Our comprehensive preclinical efficacy and safety data support progressing SGR-4174 to clinical development to treat KRAS mutant cancers."

Combination therapy • Preclinical • Colorectal Cancer • Lung Cancer • Oncology • Solid Tumor • EGFR • KRAS

SOS1 inhibitor BMS-986509 and EGFR inhibitor combinations are synergistic with adagrasib in KRAS G12C mutant tumor organoid models (ESMO 2025) - P1/2 | "Conclusions Ultimately, these data may facilitate the identification of novel biomarkers, inform on indication expansion, and identify optimal combination strategies. BMS-986509 is currently being evaluated in a FIH trial as a monotherapy and in combination with adagrasib (NCT05578092) in patients with advanced solid tumors harboring a KRAS G12C mutation."

Oncology • Solid Tumor • KRAS

Schrödinger Presents New Preclinical Data at AACR Annual Meeting (Businesswire) - "SGR-4174 Data at AACR: The poster (Abstract #4376)...includes preclinical data demonstrating the superior binding, selectivity, and drug-like properties of SGR-4147 compared to MRTX0902 as assessed via comprehensive in vitro potency, ADME, and safety assays. The preclinical data for SGR-4174 also show robust suppression of the RAS signaling pathway and potent cell killing activity across multiple cancer types harboring diverse KRAS mutations as well as EGFR and SOS1 mutations. SGR-4174 monotherapy achieved dose-dependent target engagement and tumor growth inhibition and induced tumor shrinkage when used in combination with MEK or KRAS inhibitors in preclinical models of pancreatic and non-small cell lung cancer."

Preclinical • Non Small Cell Lung Cancer • Pancreatic Cancer

Schrödinger to Present Preclinical Data at AACR Annual Meeting (Businesswire) - "The SGR-4174 presentation will include data characterizing SGR-4174 in preclinical oncology models. The SOS1 protein plays a critical role in the activation and regulation of the KRAS gene. Inhibition of SOS1 is considered a potential therapeutic combination strategy for the treatment of KRAS-driven cancers. Preclinical data suggest SGR-4174 has a differentiated profile and support its continued development as a potential therapy for patients with KRAS mutant cancers and in rare diseases arising from KRAS pathway mutations. This is the first preclinical data presentation for SGR-4174."

Preclinical • Solid Tumor

The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading. (PubMed, Mol Cancer Ther) - "MRTX0902 augmented the antitumor activity of the KRAS G12C inhibitor adagrasib when dosed in combination in eight out of twelve KRAS G12C-mutant human non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) xenograft models. Lastly, combined vertical inhibition of RTK/MAPK pathway signaling by MRTX0902 with inhibitors of EGFR or RAF/MEK led to greater downregulation of pathway signaling and improved antitumor responses in KRAS-MAPK pathway-mutant models. These studies demonstrate the potential clinical application of dual inhibition of SOS1 and KRAS G12C and additional SOS1 combination strategies that will aide in the understanding of SOS1 and RTK/MAPK biology in targeted cancer therapy."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • KRAS • NF1 • PTEN

Schrödinger Reports First Quarter 2024 Financial Results (Businesswire) - "Today Schrödinger announced that the rights to the SOS1 inhibitor discovered and developed as part of the collaboration with Bristol Myers Squibb have reverted to Schrödinger based on portfolio prioritization decisions at BMS. In 2023, Schrödinger completed and delivered a development candidate, and BMS had been conducting IND-enabling studies."

Licensing / partnership • Solid Tumor