Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein–Protein Interaction

Ketcham, John M.; Haling, Jacob R.; Khare, Shilpi; Bowcut, Vickie; Briere, David; Burns, Aaron C.; Gunn, Robin Jones; Ivetac, Anthony; Kuehler, Jon; Kulyk, Svitlana; Laguer, Jade; Lawson, J. David; Moya, Krystal; Nguyen, Natalie; Rahbæk, Lisa; Saechao, Barbara; Smith, Christopher R.; Sudhakar, Niranjan; Thomas, Nicole C.; Vegar, Laura; Vanderpool, Darin; Wang, Xiaolun; Yan, Larry; Olson, Peter; Christensen, James G.; Marx, Matthew A.

doi:10.1021/acs.jmedchem.2c00741

Cited by 55 publications

(49 citation statements)

References 42 publications

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“…Both small-molecule inhibitors and agonists have been developed to modulate SOS1 function. − Recently reported SOS1 inhibitors such as BAY293 and BI3406 were able to disrupt SOS1:KRAS interaction and demonstrated antiproliferative activity in various cancer lines. , However, SOS1 inhibitors as a single agent were less effective in inhibiting RAS -driven CRC cell growth, which required combination with a MEK inhibitor for enhanced in vivo activity in CRC . SOS1 inhibitors in preclinical studies only showed an additive effect to enhance the activity of KRAS G12C inhibitors in KRAS G12C cancers . In addition, a series of SOS1 agonists targeting the same binding site with SOS1 inhibitors were designed and synthesized using a fragment-based drug discovery strategy. − ,, However, their binding affinity to SOS1 was much lower than existing SOS1 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…16 SOS1 inhibitors in preclinical studies only showed an additive effect to enhance the activity of KRAS G12C inhibitors in KRAS G12C cancers. 18 In addition, a series of SOS1 agonists targeting the same binding site with SOS1 inhibitors were designed and synthesized using a fragment-based drug discovery strategy. [10][11][12][13]15,17 However, their binding affinity to SOS1 was much lower than existing SOS1 inhibitors.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Also, it has been reported that this interaction can also be fulfilled by phthalazine and 2,4,6-triaza-2-indanyl groups in other reported SOS1 inhibitors. 18,25 We then performed protein−protein docking of BI68BSbound SOS1 with lenalidomide-bound cereblon to determine the optimal length and conformation of the linkers of the SOS1 PROTAC degraders. In silico modeling of the interactions between proteins of interest and E3 ligases, especially cereblon, favored conformations of ternary complexes, which are putative intermediates of targeted protein degradation induced by PROTAC.…”

Section: ■ Introductionmentioning

confidence: 99%

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Development of SOS1 Inhibitor-Based Degraders to Target KRAS-Mutant Colorectal Cancer

et al. 2022

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Direct blockade of KRAS driver mutations in colorectal cancer (CRC) has been challenging. Targeting SOS1, a guanine nucleotide exchange factor, has arisen as an attractive approach for KRAS-mutant CRC. Here, we describe the development of novel SOS1 degraders and their activity in patient-derived CRC organoids (PDO). The design of these degraders as proteolysis-targeting chimera was based on the crystal structures of cereblon and SOS1. The synthesis used the 6-and 7-OH groups of a quinazoline core as anchor points to connect lenalidomide. Fifteen compounds were screened for SOS1 degradation. P7 was found to have up to 92% SOS1 degradation in both CRC cell lines and PDOs with excellent specificity. SOS1 degrader P7 demonstrated superior activity in inhibiting CRC PDO growth with an IC 50 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.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Development of SOS1 Inhibitor-Based Degraders to Target KRAS-Mutant Colorectal Cancer

et al. 2022

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“…5 In addition to small molecule SOS1 agonists developed by Fesik and colleagues, 6–11 a few of the SOS1 inhibitors have also been discovered including BAY293, BI3406, MRTX0902 and others. 12–16 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%

“…12,18,19 In the latter case, SOS1 inhibitor can enhance KRAS G12C inhibitor binding to GDP-bound KRAS, decrease KRAS G12C activation, and thus suppress oncogenic signaling. 16 As to predictive markers, previous studies showed that SOS1 inhibitor as a single agent is active in cell lines, especially NSCLC cell lines with EGFR and KRAS G12/13 mutations instead of KRAS Q61 and BRAF type I/II mutations. 12,13,19 But these findings were without further characterizations in patient-relevant cancer models.…”

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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KRAS Inhibitors

2023

Molecules Engineered Against Oncogenic Proteins and Cancer

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Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein–Protein Interaction

Cited by 55 publications

References 42 publications

Development of SOS1 Inhibitor-Based Degraders to Target KRAS-Mutant Colorectal Cancer

Development of SOS1 Inhibitor-Based Degraders to Target KRAS-Mutant Colorectal Cancer

The translational role of SOS1 in colorectal cancer

KRAS Inhibitors

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