BI-3406 / Boehringer Ingelheim, Novo Nordisk - LARVOL DELTA

Structural and Biophysical Characterization of Aminobenzo[d]isothiazole 1,1-Dioxide SOS1 Ligands. (PubMed, ACS Med Chem Lett) - "Rather than being dominated by sulfone-mediated contacts, SOS1 recognition is primarily driven by hydrophobic and aromatic packing within the canonical pocket, a conserved ligand NH hydrogen bond to Asn879, and π-π stacking with Tyr884, recapitulating key features of BI-3406 binding. Comparative analysis further delineates vector requirements for productive engagement of KRAS-facing regions, providing a structure-based framework for future optimization of aminobenzo-[d]-isothiazole 1,1-dioxide SOS1 ligands."

Journal • Oncology • KRAS

Benefits and challenges of adding BKM120 to a BI-3406 plus trametinib combination therapy. (PubMed, BMC Cancer) - "The addition of BKM120 to the combination of BI-3406 and trametinib provides minimal therapeutic benefit while introducing significant adverse effects, underscoring the need for caution when considering clinical applications."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8 • CDKN2A • KRAS • PD-L1

Computational insights on the molecular interplay between KRas (G12D mutation) and SOS1 modulated by the inhibitor BI-3406. (PubMed, PLoS Comput Biol) - "The change of binding affinity makes the catalytic pocket of SOS1 prefer to KRasGTP·Mg2+ and inhibits the growth of G12D-mutant KRas-driven tumors. These mechanistic insights provide valuable information for designing SOS1-co-targeting inhibitors to potentiate antitumor efficacy against G12D-mutated KRas."

Journal • Oncology • KRAS

Characterization of a panel of CRISPR/Cas9 engineered KRAS G12C inhibitor-resistant tumor models (AACR 2024) - "In vitro, the parental and mutated cells were treated with either AMG510 and MRTX849 and cell viability was measured by CellTiter-Glo. CRISPR/Cas9 engineered second site KRAS mutations in cells harboring KRAS G12C mutation displayed a differentially resistant profile to KRAS G12C inhibitors. Thus, H95D/Q/R, R68S and Y96D can be used as preclinical inhibitor-resistant models to evaluate clinical strategies to overcome resistance to KRAS-targeted therapies."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • MIA

Discovery and Characterization of HH100937, a potent and selective SOS1 inhibitor demonstrates synergistic efficacy in combination with KRAS/MAPK therapies (AACR 2024) - "HH100937 exhibited lower IC50s than BI-3406 and MTRX0902 in blocking ERK phosphorylation and cancer cell proliferation, leading to better anti-tumor efficacies in xenografts than reference compounds at same doses. HH100937 also showed synergistic effect with AMG510 in cancer cells with KRAS G12C mutation but refractory to AMG510...Our SOS1 inhibitor also exhibited synergistic effect with HH2710, a clinical-stage ERK inhibitor, in a broad panel of cancer cells with KRAS mutations.The pharmacological potency of HH100937 was highly selective over SOS2, other kinases tested or other targets in a safety panel of 47 targets...HH100937 also showed favorable DMPK properties in mice, rats and dogs, and acceptable safety profiles in vitro.Taken together, HH100937 is a highly potent and selective SOS1 inhibitor with better anti-tumor activities than some SOS1 inhibitors at clinical stage. It can be developed as mono therapy or in combination with other KRAS/MAPK targeting therapies."

Clinical • Combination therapy • Late-breaking abstract • Oncology • KRAS

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

Comparative effects of SOS1 inhibitor with IL-6 blockade and their combination on Kras mutant lung cancer (AACR 2024) - "Accordingly, in this study we used a mouse model of KRAS mutant LUAD (CC-LR) to compare the therapeutic effects of BI-3406, IL-6 blockade, and MEK inhibitor (trametinib). Hence, we conclude that further adjustment of the treatment regimen (doses, interval, duration) may allow to obtain improved anti-tumor efficacy with these combinations. Overall, this study provides a new research perspective for the improvement of currently available treatment modalities for patients with Kras mutant lung cancer that could be further explored preclinically."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8 • IFNG • IL10 • KRAS • STAT3

MRAS the forgotten member of the GTPase superfamily plays a role in KRASG12Ci resistance (AACR 2024) - "Pathway suppression was deepened by combining adagrasib with either a SOS1i (e.g. BI-3406) or SHP2i (e.g. TNO155) resulting in enhanced anti-tumor effects observed in the KRASG12Ci-resistant models. Our findings underscore the role of MRAS in acquired resistance in KRASG12Ci and the potential to overcome this with vertical pathway combinations, such as SOS1i or SHP2i."

Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Rational design of a small-molecule inhibitor targeting the allosteric site of sos1 in oncogenic k-ras pancreatic cancer (AACR 2024) - "Compared to the SOS1 catalytic inhibitor, BI3406, our inhibitors showed better selectivity for KRAS mutant pancreatic cancer cells vs. WT KRAS cells. These studies establish a proof of principle for the rational design of small molecule inhibitors targeting an oncogenic Kras specific allosteric site of SOS1 and provide a novel therapeutic concept to target KRAS-driven tumors more effectively."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant cancer (AACR 2024) - "The recent development of novel SOS1 inhibitors (SOS1i), including BI-3406, that block interaction between SOS1 and RAS, presents a potential therapy for SOS1-driven cancers...The tumor-suppressive effects of SOS1i in these models were comparable to or stronger than the effects of SHP2i or MEKi. Thus, our results suggest that SOS1 inhibition could be an effective therapeutic approach in RAS wild-type cancer patients with SOS1 mutations."

Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

RAS pathway inhibitors combined with targeted agents are active in patient-derived spheroids with oncogenic KRAS variants from multiple cancer types. (PubMed, Cancer Res Commun) - "Vertical inhibition of the RAS/MEK/ERK pathway by targeting SHP2 or SOS1 and the downstream kinases MEK (trametinib) or ERK (temuterkib) was highly effective. Inhibition of upstream tyrosine receptor kinases with nintedanib in combination with batoprotafib or BI-3406 was also effective, and in combination with sotorasib, demonstrated synergy in spheroids harboring KRAS G12C. Dual inhibition of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways by batoprotafib or sotorasib with either the mTORC1/2 inhibitor sapanisertib or the AKT inhibitor ipatasertib demonstrated combination activity, primarily in spheroids harboring KRAS G12C. The BCL-2 inhibitor venetoclax in combination with sotorasib, batoprotafib or BI-3406 resulted in additive and synergistic cytotoxicity. Lastly, concurrent inhibition of the KRAS pathway with sotorasib and batoprotafib demonstrated combination activity in spheroids containing KRAS G12C."

Journal • Oncology • KRAS

Development of SOS1-based PROTACs for KRAS-Mutant colorectal cancer (ACS-Fall 2025) - "Among them, P7 exhibited up to 92% SOS1 degradation in CRC cell lines and patient-derived organoids (PDOs), with superior potency compared to the SOS1 inhibitor BI3406. This work highlights SOS1-targeted protein degradation as a viable therapeutic strategy for KRAS-mutant CRC."

Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • KRAS

Development and biological evaluation of novel SOS1 inhibitors featuring 5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one scaffold. (PubMed, Bioorg Med Chem Lett) - "Among these, A15f and B5a emerged as the most potent compounds comparable to BI-3406...Molecular docking revealed that these two compounds shared a conserved binding mode with SOS1, similar to the reported inhibitors. These findings provide foundation for further development of SOS1-targeted anticancer therapeutics and offer valuable insights for structural optimization of this novel class of inhibitors."

Journal • Hematological Malignancies • Leukemia • Oncology • KRAS

Distinct roles of SOS1 and SOS2 in lipid metabolism and tumorigenesis: implications for therapeutic targeting in cancer and metabolic disorders (EASL 2025) - "SVF and MEF cells were treated with 4-hydroxytamoxifen (4OHT) and then exposed to adipogenic induction media...For therapeutic evaluation, the SOS1-RAS inhibitor BI-3406 was tested alone and in combination with sorafenib... SOS1 emerges as a potential therapeutic target due to its ability to reduce lipid accumulation, thereby protecting the liver from steatosis. Moreover, HCC experiments highlight a protective role of SOS1 during early tumorigenesis. In contrast, SOS2 is associated with increased tumor burden."

Genetic Disorders • Hepatocellular Cancer • Metabolic Disorders • Obesity • Oncology • Solid Tumor

Concurrent SOS1 and MEK suppression inhibits signaling and growth of NF1-null melanoma (EADO-WCM 2025) - "Results We show that avutometinib, a MEK inhibitor that limits MEK phosphorylation and ERK reactivation, is more effective in the NF1-null context than earlier inhibitors like trametinib and PD-901/mirdametinib. Conclusions Together, BI-3406 and avutometinib specifically target NF1-null melanoma cells. These preclinical findings provide a strong foundation for clinical evaluation of this drug combination[1]."

IO biomarker • Melanoma • Oncology • Solid Tumor • BRAF • NF1

SOS1 inhibitor BI-3406 shows in vivo antitumor activity akin to genetic ablation and synergizes with a KRASG12D inhibitor in KRAS LUAD. (PubMed, Proc Natl Acad Sci U S A) - "Furthermore, markedly stronger, synergistic antitumor effects were observed upon concomitant treatment with BI-3406 and MRTX1133 in the same in vivo LUAD mouse model. Our data confirm SOS1 as an actionable therapy target in RAS-dependent cancers and suggest that BI-3406 treatment may yield clinical benefit both as monotherapy or as a potential combination partner for multiple RAS-targeting strategies."

Journal • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Characterization of the BH1406 non-small cell lung cancer (NSCLC) cell line carrying an activating SOS1 mutation. (PubMed, Transl Lung Cancer Res) - "Besides BAY-293, BH1406 cells proved to be sensitive to the SOS1 inhibitors MRTX0902 and BI-3406...Additionally, the PI3K inhibitor dactolisib, the GSK-3 inhibitor BI-5521 as well as the bromodomain protein-directed PROTAC ARV-771 inhibited the growth of BH1406 cells significantly and showed synergistic interaction with BAY-293...BH1406 cells represent a novel cellular model suitable for the molecular characterization of SOS1 druggability. Such rare oncogenic driver genes are not included in standard NGS panels and need to be detected by expanded assays like WES."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Respiratory Diseases • Solid Tumor • Targeted Protein Degradation • CHEK2 • SOS1 • STAT3

SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma. (PubMed, Cancer Res) - "Here, we identified targeting proximal receptor tyrosine kinase (RTK) signaling using the SOS1 inhibitor (SOS1i) BI-3406 as a strategy to improve responses to G12Ci treatment...Treatment with SOS1i both delayed acquired G12Ci resistance and limited the total number of resistant colonies regardless of KEAP1 and STK11 mutational status. Together, these data suggest that targeting SOS1 could be an effective strategy to both enhance G12Ci efficacy and prevent G12Ci resistance regardless of co-mutations."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KEAP1 • KRAS • STK11

Targeted Degradation of SOS1 Exhibits Potent Anticancer Activity and Overcomes Resistance in KRAS-Mutant Tumors and BCR-ABL-Positive Leukemia. (PubMed, Cancer Res) - "In this study, we developed a potent SOS1 PROTAC SIAIS562055, which was designed by connecting a CRBN ligand to an analogue of the SOS1 inhibitor BI-3406...SIAIS562055 and BCR-ABL inhibitors synergistically enhanced inhibition of ABL phosphorylation and downstream signaling, demonstrating robust antitumor activities in both mouse xenografts and primary CML patient samples. In summary, this study suggests that PROTAC-mediated SOS1 degradation represents an effective therapeutic strategy for treating not only KRAS-mutant cancers but also BCR-ABL-harboring leukemia."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • ABL1 • BCR • CRBN • KRAS

Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance. (PubMed, Nat Cancer) - "Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRASG12Ci treatment. These results suggest KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors."

Journal • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

SOS1 inhibitor BI-3406 demonstrates anti-tumor activity akin to SOS1 genetic ablation in KRASG12D mutant tumors (EACR 2024) - "Moreover, in KRASG12D allografts genetic and pharmacological inhibition of SOS1 displayed anti-tumor efficacy comparable to treatment with a KRASG12D inhibitor MRTX1133 and resulted in synergistic antitumor effect when both inhibitors were combined. Furthermore, consistent with previous genetic evidence from our laboratory, in vivo administration of BI-3406 in an immunocompetent mouse model of KRASG12D-driven lung cancer resulted in a strong reduction of lung tumor burden and significant downmodulation of the pro-tumorigenic tumor microenvironment (TME). Conclusion Our data confirm the SOS GEFs as bona fide therapeutic targets in RAS-dependent cancers and identify a therapeutic window for SOS1 pharmacological inhibition that may translate to clinical benefits through reduction of intrinsic tumor burden and impairment of extrinsic pro-tumorigenic contributions of the surrounding TME."

Lung Cancer • Oncology • Solid Tumor • KRAS

Lead Identification of Novel Naphthyridine Derivatives as Potent SOS1 Inhibitors. (PubMed, ACS Med Chem Lett) - "Oral administration of HH0043 resulted in a significant tumor inhibitory effect in a subcutaneous KRAS G12C-mutated NCI-H358 (human lung cancer cell line) xenograft mouse model, and the tumor inhibitory effect of HH0043 was superior to that of BI-3406 at the same dose (total growth inhibition, TGI: 76% vs 49%). On the basis of these results, HH0043, with a novel 1,7-naphthyridine scaffold that is distinct from currently reported SOS1 inhibitors, is nominated as the lead compound for this discovery project."

Journal • Lung Cancer • Oncology • Solid Tumor • KRAS

Sex Matters-Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer. (PubMed, Cancers (Basel)) - "The evaluated inhibitors BI-3406, trametinib and BKM120 showed synergistic effects in vitro. This combinatorial therapy reduced tumor weight more efficiently in male animals, although the drug concentrations were similar in the tumors of both sexes. These results underline the importance of sex-specific preclinical research and at the same time provide a solid basis for future studies with the tested compounds."

Journal • Preclinical • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8 • KRAS

Discovery of Five SOS2 Fragment Hits with Binding Modes Determined by SOS2 X-Ray Cocrystallography. (PubMed, J Med Chem) - "SOS2 activity is implicated in MAPK rebound when divergent SOS1 mutant cell lines are treated with the SOS1 inhibitor BI-3406; therefore, SOS2:KRAS inhibitors are of therapeutic interest. In this report, we detail a fragment-based screening strategy to identify X-ray cocrystal structures of five diverse fragment hits bound to SOS2."

Journal • KRAS

SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status. (PubMed, Proc Natl Acad Sci U S A) - "The SOS1 inhibitor BI-3406 enhanced the efficacy of trametinib and prevented trametinib resistance by targeting spheroid-initiating cells in KRAS-mutated LUAD and COAD cell lines that lacked PIK3CA comutations. Our findings demonstrate that vertical inhibition of RTK/RAS signaling is an effective strategy to prevent therapeutic resistance in KRAS-mutated cancers, but therapeutic efficacy is dependent on both the specific KRAS mutant and underlying comutations. Thus, selection of optimal therapeutic combinations in KRAS-mutated cancers will require a detailed understanding of functional dependencies imposed by allele-specific KRAS mutations."

Journal • Colorectal Cancer • Movement Disorders • Oncology • KRAS • PI3K • PIK3CA