Drug Information

Drug (ID: DG00042) and It's Reported Resistant Information

• Name: Vismodegib
• Synonyms: 879085-55-9; GDC-0449; Erivedge; 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide; Vismodegib (GDC-0449); HhAntag691; GDC0449; GDC 0449; UNII-25X868M3DS; CHEMBL473417; CHEBI:66903; 25X868M3DS; NSC755986; AK-77261; 2-chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]-4-(methylsulfonyl)benzamide; C19H14Cl2N2O3S; 2-chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide; 2-chloro-n-(4-chloro-3-(2-pyridinyl)phenyl)-4-(methylsulfonyl)benzamide; Erivedge (TN); Vismodegib (SHH inhibitor); Gdc-0449
• Indication:
  In total 2 Indication(s)
  Basal cell carcinoma [ICD-11: 2C32]; Approved; [1]
  Brain cancer [ICD-11: 2A00]; Phase 2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Basal cell carcinoma [ICD-11: 2C32]; [2]
  Gorlin syndrome [ICD-11: LD24]; [3]
• Target: Smoothened homolog (SMO); SMO_HUMAN; [1]
• Formula: C19H14Cl2N2O3S
• IsoSMILES: CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl
• InChI: 1S/C19H14Cl2N2O3S/c1-27(25,26)13-6-7-14(17(21)11-13)19(24)23-12-5-8-16(20)15(10-12)18-4-2-3-9-22-18/h2-11H,1H3,(H,23,24)
• InChIKey: BPQMGSKTAYIVFO-UHFFFAOYSA-N
• PubChem CID: 24776445
• ChEBI ID: CHEBI:66903
• TTD Drug ID: D03EDQ
• VARIDT ID: DR00234
• INTEDE ID: DR1698
• DrugBank ID: DB08828

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Basal cell carcinoma [ICD-11: 2C32]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Smoothened homolog (SMO) [1]

• Molecule Alteration: Missense mutation; p.W535R
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Key Molecule: Smoothened homolog (SMO) [1]

• Molecule Alteration: Missense mutation; p.W535L
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Key Molecule: Smoothened homolog (SMO) [1]

• Molecule Alteration: Missense mutation; p.W281C
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Key Molecule: Smoothened homolog (SMO) [1]

• Molecule Alteration: Missense mutation; p.V321A
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Key Molecule: Smoothened homolog (SMO) [1]

• Molecule Alteration: Missense mutation; p.S533N
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Key Molecule: Smoothened homolog (SMO) [1]

• Molecule Alteration: Missense mutation; p.Q477E
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Key Molecule: Smoothened homolog (SMO) [1]

• Molecule Alteration: Missense mutation; p.H231R
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Key Molecule: Smoothened homolog (SMO) [1]

• Molecule Alteration: Missense mutation; p.F460L
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Key Molecule: Smoothened homolog (SMO) [1]

• Molecule Alteration: Missense mutation; p.D473N
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Key Molecule: Smoothened homolog (SMO) [1]

• Molecule Alteration: Missense mutation; p.D473H
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Key Molecule: Smoothened homolog (SMO) [1]

• Molecule Alteration: Missense mutation; p.D473G
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Paired-end high throughput RNA sequencing assay; Whole exome sequencing assay; whole genome sequencing assay
• Mechanism Description: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition.

Key Molecule: Smoothened homolog (SMO) [4]

• Molecule Alteration: Missense mutation; p.V321M
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Whole exome sequencing assay; Pyrosequencing assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: Genomic analysis of tumor biopsies revealed vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels.

Key Molecule: Smoothened homolog (SMO) [4]

• Molecule Alteration: Missense mutation; p.T241M
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Whole exome sequencing assay; Pyrosequencing assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: Genomic analysis of tumor biopsies revealed vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels.

Key Molecule: Smoothened homolog (SMO) [4]

• Molecule Alteration: Missense mutation; p.C469Y
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Whole exome sequencing assay; Pyrosequencing assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: Genomic analysis of tumor biopsies revealed vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels.

Key Molecule: Smoothened homolog (SMO) [4]

• Molecule Alteration: Missense mutation; p.A459V
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• In Vitro Model: Human skin tissue; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole exome sequencing assay; Pyrosequencing assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: Genomic analysis of tumor biopsies revealed vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels.

Key Molecule: Smoothened homolog (SMO) [5]

• Molecule Alteration: Missense mutation; p.G497W
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: In silico analysis demonstrated that SMOG497W undergoes a conformational rearrangement resulting in a partial obstruction of the protein drug entry site, whereas the SMO D473Y mutation induces a direct effect on the binding site geometry leading to a total disruption of a stabilizing hydrogen bond network. Thus, the G497W and D473Y SMO mutations may represent two different mechanisms leading to primary and secondary resistance to vismodegib, respectively.

Key Molecule: Smoothened homolog (SMO) [5]

• Molecule Alteration: Missense mutation; p.D473Y
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: In silico analysis demonstrated that SMOG497W undergoes a conformational rearrangement resulting in a partial obstruction of the protein drug entry site, whereas the SMO D473Y mutation induces a direct effect on the binding site geometry leading to a total disruption of a stabilizing hydrogen bond network. Thus, the G497W and D473Y SMO mutations may represent two different mechanisms leading to primary and secondary resistance to vismodegib, respectively.

Key Molecule: Smoothened homolog (SMO) [2]

• Molecule Alteration: Missense mutation; p.W281L
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Exon sequencing assay
• Experiment for Drug Resistance: Magnetic resonance imaging assay
• Mechanism Description: Upregulation of Hedgehog (Hh) signaling is crucial in the development of almost all BCCs. Vismodegib resistance in medulloblastoma is caused by acquired mutations in SMO.

Key Molecule: Smoothened homolog (SMO) [2]

• Molecule Alteration: Missense mutation; p.V321M
• Resistant Disease: Basal cell carcinoma [ICD-11: 2C32.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Exon sequencing assay
• Experiment for Drug Resistance: Magnetic resonance imaging assay
• Mechanism Description: Upregulation of Hedgehog (Hh) signaling is crucial in the development of almost all BCCs. Vismodegib resistance in medulloblastoma is caused by acquired mutations in SMO.

References

• Ref 1: Smoothened variants explain the majority of drug resistance in basal cell carcinoma. Cancer Cell. 2015 Mar 9;27(3):342-53. doi: 10.1016/j.ccell.2015.02.002.
• Ref 2: Acquired resistance to the Hedgehog pathway inhibitor vismodegib due to smoothened mutations in treatment of locally advanced basal cell carcinoma. J Am Acad Dermatol. 2014 Nov;71(5):1005-8. doi: 10.1016/j.jaad.2014.08.001. Epub 2014 Sep 4.
• Ref 3: Can hair re-growth be considered an early clinical marker of treatment resistance to Hedgehog inhibitors in patients with advanced basal cell carcinoma A report of two cases .J Eur Acad Dermatol Venereol. 2016 Oct;30(10):1726-1729. doi: 10.1111/jdv.13754. Epub 2016 Jul 27. 10.1111/jdv.13754
• Ref 4: Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma. Cancer Cell. 2015 Mar 9;27(3):327-41. doi: 10.1016/j.ccell.2015.02.001.
• Ref 5: Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma. Mol Oncol. 2015 Feb;9(2):389-97. doi: 10.1016/j.molonc.2014.09.003. Epub 2014 Sep 26.