Drug Information

Drug (ID: DG01646) and It's Reported Resistant Information

• Name: RAF709
• Synonyms: RAF709; 1628838-42-5; RAF-709; N-[6-methyl-5-[5-morpholin-4-yl-6-(oxan-4-yloxy)pyridin-3-yl]pyridin-3-yl]-3-(trifluoromethyl)benzamide; N-{2-Methyl-5'-(Morpholin-4-Yl)-6'-[(Oxan-4-Yl)oxy][3,3'-Bipyridin]-5-Yl}-3-(Trifluoromethyl)benzamide; CHEMBL3962812; SCHEMBL16035801; BDBM202784; BCP19140; EX-A1298; s8690; AKOS030632027; CCG-269969; CS-6074; BS-15948; HY-100510; J3.655.460F; A16842; C73133; US9242969, 131; 92J; N-(2-methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide; N-(2-Methyl-5'-morpholino-6'-(tetrahydro-2H-pyran-4-yloxy)-3,3'-bipyridin-5-yl)-3-(trifluoromethyl)benzamide
• Target: .; NOUNIPROTAC; [1]
• Formula: 6
• IsoSMILES: CC1=C(C=C(C=N1)NC(=O)C2=CC(=CC=C2)C(F)(F)F)C3=CC(=C(N=C3)OC4CCOCC4)N5CCOCC5
• InChI: InChI=1S/C28H29F3N4O4/c1-18-24(15-22(17-32-18)34-26(36)19-3-2-4-21(13-19)28(29,30)31)20-14-25(35-7-11-38-12-8-35)27(33-16-20)39-23-5-9-37-10-6-23/h2-4,13-17,23H,5-12H2,1H3,(H,34,36)
• InChIKey: FYNMINFUAIDIFL-UHFFFAOYSA-N
• PubChem CID: 90408826

Type(s) of Resistant Mechanism of This Drug

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Lung cancer [ICD-11: 2C25]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [1]

• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Targeting CRAF could sensitize response to MEK inhibitors in KRAS-mutant tumors. In addition to targeting multiple signaling nodes within the MAPK pathway to maximize both level and duration of signaling inhibition, combining RAF709 with inhibitors targeting the upstream RTK activation such as EGFR, bypass mechanisms such as YAP1 or targeting prosurvival BCL2 family members, may further enhance efficacy and reduce the development of drug resistance.

Melanoma [ICD-11: 2C30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [1]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Targeting CRAF could sensitize response to MEK inhibitors in KRAS-mutant tumors. In addition to targeting multiple signaling nodes within the MAPK pathway to maximize both level and duration of signaling inhibition, combining RAF709 with inhibitors targeting the upstream RTK activation such as EGFR, bypass mechanisms such as YAP1 or targeting prosurvival BCL2 family members, may further enhance efficacy and reduce the development of drug resistance.

Key Molecule: GTPase Nras (NRAS) [1]

• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Targeting CRAF could sensitize response to MEK inhibitors in KRAS-mutant tumors. In addition to targeting multiple signaling nodes within the MAPK pathway to maximize both level and duration of signaling inhibition, combining RAF709 with inhibitors targeting the upstream RTK activation such as EGFR, bypass mechanisms such as YAP1 or targeting prosurvival BCL2 family members, may further enhance efficacy and reduce the development of drug resistance.

Key Molecule: GTPase Nras (NRAS) [1]

• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Targeting CRAF could sensitize response to MEK inhibitors in KRAS-mutant tumors. In addition to targeting multiple signaling nodes within the MAPK pathway to maximize both level and duration of signaling inhibition, combining RAF709 with inhibitors targeting the upstream RTK activation such as EGFR, bypass mechanisms such as YAP1 or targeting prosurvival BCL2 family members, may further enhance efficacy and reduce the development of drug resistance.

References

• Ref 1: Antitumor Properties of RAF709, a Highly Selective and Potent Inhibitor of RAF Kinase Dimers, in Tumors Driven by Mutant RAS or BRAFCancer Res. 2018 Mar 15;78(6):1537-1548. doi: 10.1158/0008-5472.CAN-17-2033. Epub 2018 Jan 17.