An in silico drug-likeness assessment suggested that the compound has moderately favorable drug-like properties and pharmacokinetic characteristics. Altogether, our findings strongly support that, characterized by the distinctive binding modes, the recognition of novel skeletons from the carboxylic acid series could be candidates for developing promising SOS1 inhibitors.

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.

P1, N=71, Active, not recruiting, Boehringer Ingelheim | Trial primary completion date: Mar 2024 --> Oct 2024

Comparative analysis of the average binding free energies of these predicted potent compounds with known SOS1 small molecule inhibitors revealed that the identified compounds display similar or even superior predicted binding affinities compared to the known inhibitors. These findings offer valuable insights into the potential of these compounds as candidates for further development as effective anti-cancer agents.

P1/2, N=110, Recruiting, Suzhou Zelgen Biopharmaceuticals Co.,Ltd | Not yet recruiting --> Recruiting | Initiation date: Feb 2024 --> Aug 2023

P1, N=71, Active, not recruiting, Boehringer Ingelheim | Trial completion date: Mar 2024 --> Oct 2024

P1/2, N=110, Not yet recruiting, Suzhou Zelgen Biopharmaceuticals Co.,Ltd

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.

P1, N=71, Active, not recruiting, Boehringer Ingelheim | Trial completion date: Sep 2023 --> Mar 2024 | Trial primary completion date: Sep 2023 --> Mar 2024

Finally, we showed that GTP-bound RAS level underwent rebound even in BI3406-sensitive PDOs with no change of KRAS downstream effector genes, thus suggesting upregulation of guanine nucleotide exchange factor as potential cellular adaptation mechanisms to SOS1 inhibition. Taken together, our results show that high SOS1/SOS2 protein expression ratio predicts sensitivity to SOS1 inhibition and support further clinical development of SOS1-targeting agents in CRC.

6c showed a favorable pharmacokinetic profile in vivo, with a bioavailability of 65.8% and exhibited potent tumor suppression in pancreas tumor xenograft models. These intriguing results suggested that 6c has the potential to be developed as a drug candidate for KRAS-driven tumors.

Here, we designed and synthesized a series of quinazoline-based compounds, and conducted subsequent evaluations of their biological activities. Among them, the comparable compounds I-2 (IC=20nM, against SOS1) I-5 (IC=18nM, against SOS1) and I-10 (IC=8.5nM, against SOS1) have kinase activity equivalent to BAY-293 (IC=6.6nM, against SOS1), and I-10 also has cell activity equivalent to BAY-293, providing a theoretical reference for subsequent related researches on SOS1 inhibitors.

Single agent SOS1 inhibition had no significant effect in the DhhCre;Nf1 mouse model of plexiform neurofibroma, but pharmacokinetics (PK)-driven combination of selumetinib with BI-3406 significantly improved tumor parameters. Significance Statement Interfering with the RAS-MAPK cascade upstream of MEK, together with MEK inhibition, augment effects of MEK inhibition on neurofibroma volume and tumor macrophages in a preclinical model system. This study emphasizes the critical role of the RAS-MAPK pathway in controlling tumor cell proliferation and the tumor microenvironment in benign neurofibromas.

P1, N=71, Active, not recruiting, Boehringer Ingelheim | Trial completion date: Feb 2023 --> Sep 2023 | Trial primary completion date: Feb 2023 --> Sep 2023

P1, N=8, Terminated, Boehringer Ingelheim | Completed --> Terminated; Sponsor decision

P1, N=8, Completed, Boehringer Ingelheim | Terminated --> Completed

P1b/2, N=1143, Recruiting, Amgen | Trial completion date: Oct 2026 --> Jun 2027 | Trial primary completion date: Aug 2024 --> Dec 2024

P1, N=7, Completed, Mirati Therapeutics Inc. | Active, not recruiting --> Completed | N=100 --> 7 | Trial completion date: Feb 2024 --> Nov 2022 | Trial primary completion date: Nov 2023 --> Nov 2022

The synthesis used the 6- and 7-OH groups of a quinazoline core as anchor points to connect lenalidomide. SOS1 degrader P7 demonstrated superior activity in inhibiting CRC PDO growth with an IC 5 times lower than that of SOS1 inhibitor BI3406. In summary, we developed new SOS1 degraders and demonstrated SOS1 degradation as a feasible therapeutic strategy for KRAS-mutant CRC.

To conclude, SOS1 may induce the EMT by the activation of the PI3K/AKT/mTOR pathway, thereby enhancing invasion, migration and metastasis of HCC cells. These findings may expose SOS1 as a new HCC therapeutic target.

P1/2, N=225, Recruiting, Mirati Therapeutics Inc. | Not yet recruiting --> Recruiting

Toxicological investigations revealed that 13c had a lower risk of sudden cardiac death than BI-3406. Overall, 13c has been under evaluation in preclinical trials.

P1/2, N=225, Not yet recruiting, Mirati Therapeutics Inc.

P1, N=71, Active, not recruiting, Boehringer Ingelheim | Trial completion date: Sep 2022 --> Feb 2023 | Trial primary completion date: Sep 2022 --> Feb 2023

We investigated the anti-tumor efficacy of two KRAS inhibitors BI-3406 (KRAS::SOS1 inhibitor) and sotorasib (KRAS G12C inhibitor) alone or in combination with MEK1/2 inhibitor trametinib and/or PI3K inhibitor buparlisib in seven PDAC cell lines. As well as directly involved in RAF/MEK/ERK pathway and PI3K/AKT pathway affect cell survival. Our current study confirmed inhibition of KRAS and its downstream pathways as a potential novel therapy for PDAC and provides fundamental data for in vivo evaluations.

In particular, divergent responses for BAY-293 combinations between pancreatic and NSCLC cell lines were observed for linsitinib, superior inhibitory effects of trametinib and PD98059 in NSCLC, and lack of activity with doxorubicin in case of the pancreatic cell lines. Phosphoproteome analysis revealed inhibition of distinct signaling pathways by BAY-293 for MIA PaCa-2 on the one hand and for Aspc1 and BH1362 on the other hand. In conclusion, BAY-293 exhibits synergy with drugs in dependence of the tumor type and specific KRAS mutation.

We describe a comprehensive TME-based stratification of iCCA. Cross-species analysis establishes murine models that align closely to human iCCA for the preclinical testing of combination strategies.

Small-molecule SOS1 inhibitors showed promising anticancer potential, and the most advanced inhibitor BI 1701963 is currently under phase I clinical studies...Tumor xenograft study clearly showed the promising antitumor potency of 9d against human lung cancer. This study provides good evidence of using agonists to design SOS1 PROTACs and demonstrates that targeted SOS1 degradation represents an effective therapeutic strategy for overcoming KRAS-driven cancers.

P1a/1b, N=60, Recruiting, Boehringer Ingelheim | Trial completion date: Jan 2024 --> Jul 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

P1, N=15, Terminated, Boehringer Ingelheim | N=95 --> 15 | Trial completion date: Feb 2024 --> Apr 2022 | Suspended --> Terminated | Trial primary completion date: Jan 2024 --> Apr 2022; Sponsor decision

P1, N=8, Terminated, Boehringer Ingelheim | N=124 --> 8 | Trial completion date: Jul 2024 --> Apr 2022 | Suspended --> Terminated | Trial primary completion date: Oct 2023 --> Apr 2022; Sponsor decision

P1, N=71, Active, not recruiting, Boehringer Ingelheim | Trial completion date: May 2022 --> Sep 2022 | Trial primary completion date: May 2022 --> Sep 2022

Despite the efforts of more than four decades, not many KRAS inhibitors have been successful in obtaining clinical approval, except the very recent FDA approval for sotorasib...In view of this aspect, specific attention is required to target all other mutations as well. Accordingly, for the development of KRAS targeted therapies, the design of small molecule inhibitors that can inhibit KRAS signaling and as well as target inhibition of other signaling pathways like RAS-SOS and RAS-PI3K has to be explored extensively.

P1, N=100, Active, not recruiting, Mirati Therapeutics Inc. | Recruiting --> Active, not recruiting

P1, N=95, Suspended, Boehringer Ingelheim | Recruiting --> Suspended

P1, N=124, Suspended, Boehringer Ingelheim | Recruiting --> Suspended

Importantly, we demonstrated that the tumor growth of stably over-expressed miR-148b-3p human MG-63 cells was obviously reduced in tumor-bearing mice. These data highlighted that miR-148b-3p might be as a promising therapeutic target for OS.