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Published in final edited form as: J Med Chem. 2022 Dec 2;65(24):16432–16450. doi: 10.1021/acs.jmedchem.2c01300

Figure 6. — Effect of SOS1 degraders in colorectal cell lines and patient-derived organoid models. (A) SOS1 expression by IHC in colorectal cancer patient-derived organoid models. a. Positive control for SOS1 expression at 40x; b. Negative control for SOS1 expression at 40x. The negative controls used for the SOS1 IHC studies was the non-immune isotype-specific immunoglobulins; c. SOS1 expression of MCC19990-002 PDO after treatment with 0.2% DMSO for 24 hours at 40x; d. SOS1 expression of MCC19990-002 PDO after treatment with 1μM P7 for 24 hours at 40x; e. SOS1 expression of MCC19990-010 PDO after treatment with 0.2% DMSO for 24 hours at 40x; f. SOS1 expression of MCC19990-010 PDO after treatment with 1μM P7 for 24 hours at 40x; g. SOS1 expression of MCC19990-013 PDO after treatment with 0.2% DMSO for 24 hours at 40x; h. SOS1 expression of MCC19990-013 PDO after treatment with 1μM P7 for 24 hours at 40x. (B) H&E stain to assess morphology of colorectal cancer patient-derived organoid models. a. MCC19990-010 PDO after treatment with 0.2% DMSO for 24 hours at 40x; b. MCC19990-010 PDO after treatment with 1μM P7 for 24 hours at 40x; c. MCC19990-013 PDO after treatment with 0.2% DMSO for 24 hours at 40x; d. MCC19990-013 PDO after treatment with 1μM P7 for 24 hours at 40x. (C) Annexin V expression by IHC in colorectal cancer patient-derived organoid models. a. Negative control for Annexin V expression at 40x; b. Positive control (treated with FOLFIRI) for Annexin V expression at 40x; c. Annexin V expression of MCC19990-010 PDO after treatment with 0.2% DMSO for 24 hours at 40x; d. Annexin V expression of MCC19990-010 PDO after treatment with 1μM P7 for 24 hours at 40x; e. Annexin V expression of MCC19990-013 PDO after treatment with 0.2% DMSO for 24 hours at 40x; f. Annexin V expression of MCC19990-013 PDO after treatment with 1μM P7 for 24 hours at 40x. (D) Viability of patient-derived CRC organoid models after treatment with P7 compared to BI3406 at various concentrations for 72 hours. MCC19990-002 was resistant to both compounds. For MCC19990-006, P7 has IC₅₀ 1.4μM; BI3406 has IC₅₀ 8.5μM. For MCC19990-010, P7 has IC₅₀ 0.48μM; BI3406 has IC₅₀ 1.9μM. For MCC19990-013, P7 has IC₅₀ 1.16μM; BI3406 has IC₅₀ 6.7μM.

Figure 6. — Effect of SOS1 degraders in colorectal cell lines and patient-derived organoid models. (A) SOS1 expression by IHC in colorectal cancer patient-derived organoid models. a. Positive control for SOS1 expression at 40x; b. Negative control for SOS1 expression at 40x. The negative controls used for the SOS1 IHC studies was the non-immune isotype-specific immunoglobulins; c. SOS1 expression of MCC19990-002 PDO after treatment with 0.2% DMSO for 24 hours at 40x; d. SOS1 expression of MCC19990-002 PDO after treatment with 1μM P7 for 24 hours at 40x; e. SOS1 expression of MCC19990-010 PDO after treatment with 0.2% DMSO for 24 hours at 40x; f. SOS1 expression of MCC19990-010 PDO after treatment with 1μM P7 for 24 hours at 40x; g. SOS1 expression of MCC19990-013 PDO after treatment with 0.2% DMSO for 24 hours at 40x; h. SOS1 expression of MCC19990-013 PDO after treatment with 1μM P7 for 24 hours at 40x. (B) H&E stain to assess morphology of colorectal cancer patient-derived organoid models. a. MCC19990-010 PDO after treatment with 0.2% DMSO for 24 hours at 40x; b. MCC19990-010 PDO after treatment with 1μM P7 for 24 hours at 40x; c. MCC19990-013 PDO after treatment with 0.2% DMSO for 24 hours at 40x; d. MCC19990-013 PDO after treatment with 1μM P7 for 24 hours at 40x. (C) Annexin V expression by IHC in colorectal cancer patient-derived organoid models. a. Negative control for Annexin V expression at 40x; b. Positive control (treated with FOLFIRI) for Annexin V expression at 40x; c. Annexin V expression of MCC19990-010 PDO after treatment with 0.2% DMSO for 24 hours at 40x; d. Annexin V expression of MCC19990-010 PDO after treatment with 1μM P7 for 24 hours at 40x; e. Annexin V expression of MCC19990-013 PDO after treatment with 0.2% DMSO for 24 hours at 40x; f. Annexin V expression of MCC19990-013 PDO after treatment with 1μM P7 for 24 hours at 40x. (D) Viability of patient-derived CRC organoid models after treatment with P7 compared to BI3406 at various concentrations for 72 hours. MCC19990-002 was resistant to both compounds. For MCC19990-006, P7 has IC₅₀ 1.4μM; BI3406 has IC₅₀ 8.5μM. For MCC19990-010, P7 has IC₅₀ 0.48μM; BI3406 has IC₅₀ 1.9μM. For MCC19990-013, P7 has IC₅₀ 1.16μM; BI3406 has IC₅₀ 6.7μM.