Discovery of Orally Bioavailable SOS1 Inhibitors for Suppressing KRAS-Driven Carcinoma

He, Huan; Xu, Juan; Li, Yuanyuan; Fang, Huaxiang; Liu, Yi; Zhang, Silong

doi:10.1021/acs.jmedchem.2c00986

Cited by 18 publications

(12 citation statements)

References 29 publications

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“…To continue their efforts, the authors designed and synthesized compound 39 (SOS1 IC 50 = 3.9 nM, DLD-1 p-ERK IC 50 = 21 nM) with an expanded C-ring to demonstrate the comparable inhibitory activities to those of 38 (SOS1 IC 50 = 8.4 nM, DLD-1 p-ERK IC 50 = 13 nM). 96 The PK studies of 39 (T 1/2 = 6.68 h, Cl = 11.3 mL/min/kg) in beagle dogs showed a longer half-life and lower elimination rate than BI-3406 (T 1/2 = 3.07 h, Cl = 20 mL/min/kg), leading to a fascinating bioavailability of 87%. Notably, compound 39 showed a lower risk of sudden cardiac death than BI-3406 in the toxicological investigations.…”

Section: Sos1 Inhibitorsmentioning

confidence: 99%

“…The similar binding model between 38 and BI-3406 toward SOS1 suggested that the cyclopropane and the D-ring moiety of 38 mimic the tetrahydrofuran counterpart of BI-3406 . To continue their efforts, the authors designed and synthesized compound 39 (SOS1 IC 50 = 3.9 nM, DLD-1 p -ERK IC 50 = 21 nM) with an expanded C-ring to demonstrate the comparable inhibitory activities to those of 38 (SOS1 IC 50 = 8.4 nM, DLD-1 p -ERK IC 50 = 13 nM) . The PK studies of 39 ( T 1/2 = 6.68 h, Cl = 11.3 mL/min/kg) in beagle dogs showed a longer half-life and lower elimination rate than BI-3406 ( T 1/2 = 3.07 h, Cl = 20 mL/min/kg), leading to a fascinating bioavailability of 87%.…”

Section: Small Molecules Targeting Sos1mentioning

confidence: 99%

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Development of Son of Sevenless Homologue 1 (SOS1) Modulators To Treat Cancers by Regulating RAS Signaling

et al. 2023

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Son of sevenless homologue 1 (SOS1) protein is universally expressed in cells and plays an important role in the RAS signaling pathway. Specifically, this protein interacts with RAS in response to upstream stimuli to promote guanine nucleotide exchange in RAS and activates the downstream signaling pathways. Thus, targeting SOS1 is a new approach for treating RAS-driven cancers. In this Perspective, we briefly summarize the structural and functional aspects of SOS1 and focus on recent advances in the discovery of activators, inhibitors, and PROTACs that target SOS1. This review aims to provide a timely and updated overview on the strategies for targeting SOS1 in cancer therapy.

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Section: Sos1 Inhibitorsmentioning

confidence: 99%

Section: Small Molecules Targeting Sos1mentioning

confidence: 99%

Development of Son of Sevenless Homologue 1 (SOS1) Modulators To Treat Cancers by Regulating RAS Signaling

et al. 2023

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“…5 In addition to small molecule SOS1 agonists developed by Fesik and colleagues, [6][7][8][9][10][11] a few of the SOS1 inhibitors have also been discovered including BAY293, BI3406, MRTX0902 and others. [12][13][14][15][16] BAY293 was able to disrupt SOS1-KRAS interaction and demonstrated cellular activity in various cancer cell lines in vitro. 12 BI3406 was the first potent SOS1 inhibitor with single digit nanomolar binding affinity and in vivo activities.…”

Section: Introductionmentioning

confidence: 99%

The translational role of SOS1 in colorectal cancer

Alem

Yang

Beato

et al. 2022

Preprint

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Background It has been challenging to develop agents directly targeting KRAS driver mutations in colorectal cancer (CRC). Recent efforts have focused on developing inhibitors targeting SOS1 as an attractive approach for KRAS-mutant cancers. Here, we aimed to study the translational role of SOS1 in CRC using patient-derived organoids (PDOs). Method In this study, we used CRC PDOs as preclinical models to evaluate their sensitivity to SOS1 inhibitor BI3406 and its cellular effects. We utilized large CRC datasets including GENIE cohort, TCGA PanCancer Atlas, and CPTAC-2 cohort to study the significance of molecular alterations of SOS1 in CRC. To identify potential predictive markers, we performed immunohistochemistry (IHC) on CRC tissue for SOS1/2 protein expression and RNA sequencing to identify discriminative gene sets for sensitivity to SOS1 inhibition. The findings were validated by DepMap data for SOS1 dependency. Result Background It has been challenging to develop agents directly targeting KRAS driver mutations in colorectal cancer (CRC). Recent efforts have focused on developing inhibitors targeting SOS1 as an attractive approach for KRAS-mutant cancers. Here, we aimed to study the translational role of SOS1 in CRC using patient-derived organoids (PDOs). Method In this study, we used CRC PDOs as preclinical models to evaluate their sensitivity to SOS1 inhibitor BI3406 and its cellular effects. We utilized large CRC datasets including GENIE cohort, TCGA PanCancer Atlas, and CPTAC-2 cohort to study the significance of molecular alterations of SOS1 in CRC. To identify potential predictive markers, we performed immunohistochemistry (IHC) on CRC tissue for SOS1/2 protein expression and RNA sequencing to identify discriminative gene sets for sensitivity to SOS1 inhibition. The findings were validated by DepMap data for SOS1 dependency. Result CRC PDOs instead of cell lines had differential sensitivities to BI3406. There was a significant correlation between SOS1 and SOS2 mRNA expressions (Spearman's Rho 0.56, p<0.001). SOS1/2 protein expression by IHC were universal with heterogeneous patterns in cancer cells but only minimal to none in surrounding non-malignant cells. SOS1 protein expression was associated with worse overall survival in patients with RAS/RAF mutant CRC (p=0.04). We also found that SOS1/SOS2 protein expression ratio > 1 by IHC (p=0.03) instead of KRAS mutation (p=1) was a better predictive marker to BI3406 sensitivity of CRC PDOs. This was concordant with the significant correlation between SOS1/SOS2 protein expression ratio by mass spectrometry and SOS1 dependency score. RNA-seq and gene set enrichment analysis revealed differentially expressed genes and 7 enriched gene sets involving cholesterol homeostasis, epithelial mesenchymal transition, and TNFα/NFκB signaling in BI3406-resistant CRC PDOs. We further discovered that GTP-bound RAS level underwent rebound at 48 hours upon treatment with BI3406 even in BI3406-sensitive PDOs with no change of KRAS effector genes downstream. Cellular adaptation mechanisms to SOS1 inhibition may involve upregulation of SOS1/2 mRNA and SOS1 protein expressions, which may be overcome by SOS1 knockdown/degradation or synergistic effect of BI3406 with trametinib. Conclusion In summary, CRC PDOs could serve as better models for translational study of SOS1 in CRC. High SOS1 protein expression was a worse prognostic factor in CRC. High SOS1/SOS2 protein expression ratio predicted sensitivity to SOS1 inhibition and dependency. Our preclinical findings supported further clinical development of SOS1-targeting agents in CRC. Conclusion In summary, CRC PDOs could serve as better models for translational study of SOS1 in CRC. High SOS1 protein expression was a worse prognostic factor in CRC. High SOS1/SOS2 protein expression ratio predicted sensitivity to SOS1 inhibition and dependency. Our preclinical findings supported further clinical development of SOS1-targeting agents in CRC.

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“…Another compound MRTX0902 ( 5 ) developed by Mirati Therapeutics with a phthalazine core also reached the clinical trial stage recently . Similar works have also been reported by Revolution Medicine and He et al for the SOS1 inhibitor tool RMC-0331 ( 6 ) carrying a pyrrolo[3,4- d ]pyrimidin scaffold and the tetracyclic quinazoline SOS1 inhibitors (e.g., 7 ) with favorable druglike properties, respectively …”

mentioning

confidence: 99%

“…20 Similar works have also been reported by Revolution Medicine and He et al for the SOS1 inhibitor tool RMC-0331 ( 6) carrying a pyrrolo [3,4-d]pyrimidin scaffold 21 and the tetracyclic quinazoline SOS1 inhibitors (e.g., 7) with favorable druglike properties, respectively. 22 Our group's research interests focus on the discovery of small molecule probes targeting the KRAS-MAPK pathway. Using the scaffold hopping strategy, we also designed a class of SOS1 inhibitors on the basis of pyrido [2,3-d]pyrimidin-7-one, which is a privileged scaffold in drug development.…”

mentioning

confidence: 99%

Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors

Zhou

et al. 2023

ACS Med. Chem. Lett.

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The use of small molecular modulators to target the guanine nucleotide exchange factor SOS1 has been demonstrated to be a promising strategy for the treatment of various KRAS-driven cancers. In the present study, we designed and synthesized a series of new SOS1 inhibitors with the pyrido[2,3-d]pyrimidin-7one scaffold. One representative compound 8u showed comparable activities to the reported SOS1 inhibitor BI-3406 in both the biochemical assay and the 3-D cell growth inhibition assay. Compound 8u obtained good cellular activities against a panel of KRAS G12-mutated cancer cell lines and inhibited downstream ERK and AKT activation in MIA PaCa-2 and AsPC-1 cells. In addition, it displayed synergistic antiproliferative effects when used in combination with KRAS G12C or G12D inhibitors. Further modifications of the new compounds may give us a promising SOS1 inhibitor with favorable druglike properties for use in the treatment of KRAS-mutated patients.

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Discovery of Orally Bioavailable SOS1 Inhibitors for Suppressing KRAS-Driven Carcinoma

Cited by 18 publications

References 29 publications

Development of Son of Sevenless Homologue 1 (SOS1) Modulators To Treat Cancers by Regulating RAS Signaling

Development of Son of Sevenless Homologue 1 (SOS1) Modulators To Treat Cancers by Regulating RAS Signaling

The translational role of SOS1 in colorectal cancer

Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors

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