On April 28, 2025 Schrödinger, Inc. (Nasdaq: SDGR) reported preclinical data on SGR-3515, its investigational Wee1/Myt1 co-inhibitor today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025 (Press release, Schrodinger, APR 28, 2025, View Source [SID1234652283]). The data demonstrated that SGR-3515 has improved anti-tumor activity in preclinical models compared to known Wee1 and Myt1 monotherapy inhibitors. The poster also described how the dosing schedule of SGR-3515 can be optimized to preserve efficacy and minimize target-related side effects. New data was also presented on the development of a computational method that predicts the response to Wee1-based drug combinations, including in novel cancer settings such as head and neck cancers. Schrödinger expects to report initial data from the ongoing Phase 1 clinical trial of SGR-3515 in patients with advanced solid tumors in the second half of 2025.
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Additionally, Schrödinger presented its first preclinical data for SGR-4174, its SOS1 inhibitor that disrupts the interaction between SOS1 and KRAS, the most frequently mutated oncogene in human cancers. SGR-4171 demonstrated high selectivity for SOS1 over SOS2 as well as over other kinases. The data also demonstrated that SGR-4174 has strong tumor growth inhibition as a monotherapy as well as in combination with MEK or KRAS inhibitors, while maintaining a favorable safety profile. SOS1 development opportunities include cancers such as lung adenocarcinoma or RASopathies such as Neurofibromatosis Type 1.
"The preclinical data for SGR-3515 and SGR-4174 further demonstrate that molecules discovered and developed by Schrödinger have favorably differentiated molecular profiles compared to existing development-stage molecules," said Karen Akinsanya, Ph.D, president of R&D therapeutics at Schrödinger. "The preclinical profiles of these development candidates reinforce the power of our computationally-driven approach to designing molecules that meet challenging target product profiles and have the potential for meaningful benefit to patients."
SGR-3515 Data at AACR (Free AACR Whitepaper)
The poster (Abstract #3025), "Optimization of therapeutic index of SGR-3515, a first-in-class Wee1/Myt1 inhibitor through intermittent dosing for monotherapy and combination with chemotherapy in xenograft tumor models," includes preclinical data demonstrating that SGR-3515 monotherapy has superior anti-tumor activity compared to the Wee1 inhibitor ZN-c3 and the Myt1 inhibitor RP-6306 in multiple tumor models as well as synergistic efficacy when used in combination with chemotherapy. The poster also shares for the first time preclinical data demonstrating that the potential efficacy and tolerability of SGR-3515 can be optimized with three to five days of dosing, depending on the tumor type, in a two-week dosing cycle across multiple tumor settings. The optimized dosing schedule preserves efficacy while allowing for complete recovery from reversible on-target myelosuppression in preclinical tumor models.
A second poster (Abstract #3660), "Machine learning-based combination prediction for Wee1 inhibitor," presents data showing that a machine learning model, built on the integration of two large cell line combination screening studies of the Wee1 inhibitor AZD1775, successfully identified known and novel synergistic Wee1 drug combinations such as with tyrosine kinase inhibitors in ovarian and breast cancers, and with chemotherapy in head and neck or cancers. The data suggests potential for machine learning based approaches to make predictions with a high degree of confidence and gain novel insights beyond the data they are trained on.
SGR-4174 Data at AACR (Free AACR Whitepaper)
The poster (Abstract #4376), "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," 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.