Drug Information

Drug (ID: DG01667) and It's Reported Resistant Information

• Name: SB590885
• Synonyms: SB590885; 405554-55-4; SB-590885; 5-(2-(4-(2-(dimethylamino)ethoxy)phenyl)-5-(pyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-1H-inden-1-one oxime; SB 590885; (NE)-N-[5-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl]-2,3-dihydroinden-1-ylidene]hydroxylamine; (E)-5-(2-(4-(2-(dimethylamino)ethoxy)phenyl)-5-(pyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-1H-inden-1-one oxime; (E)-SB-590885; (Z)-SB-590885; SCHEMBL131578; CHEMBL477989; SCHEMBL12518520; SCHEMBL16111665; SCHEMBL17378611; EX-A612; CHEBI:131881; BCPP000070; 1H-Inden-1-one, 5-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-5-(4-pyridinyl)-1H-imidazol-4-yl]-2,3-dihydro-, oxime; 5-[2-[4-[2-(Dimethylamino)ethoxy]phenyl]-5-(4-pyridinyl)-1H-imidazol-4-yl]-2,3-dihydro-1H-inden-1-one oxime; AMY20674; BDBM50457452; NSC754362; NSC756456; s2220; SB-590885 (RAF); ZINC100061199; CCG-264947; NSC-754362; NSC-756456; (E)--(2-(dimethylamino)ethoxy)phenyl)-5-(pyridin-4-yl)-1H-imidazol-4-yl)-2,3-dihydro-1H-inden-1-one oxime; (E)-SB590885; AS-16232; (E)-SB 590885; A25514; J-501805; BRD-K78809024-001-05-7; Q27120375; Q27225284; (1E)-N-{5-[2-{4-[2-(dimethylamino)ethoxy]phenyl}-4-(pyridin-4-yl)-1H-imidazol-5-yl]-2,3-dihydro-1H-inden-1-ylidene}hydroxylamine; 5-[2-[4-[2-(Dimethylamino)ethoxy]phenyl]-5-(4-pyridinyl)-1H-imidazol-4-yl]-2,3-dihydro-1H-inden-1-one oxime;SB-590885
• Formula: 7
• IsoSMILES: CN(C)CCOC1=CC=C(C=C1)C2=NC(=C(N2)C3=CC=NC=C3)C4=CC5=C(C=C4)/C(=N/O)/CC5
• InChI: InChI=1S/C27H27N5O2/c1-32(2)15-16-34-22-7-3-19(4-8-22)27-29-25(18-11-13-28-14-12-18)26(30-27)21-5-9-23-20(17-21)6-10-24(23)31-33/h3-5,7-9,11-14,17,33H,6,10,15-16H2,1-2H3,(H,29,30)/b31-24+
• InChIKey: MLSAQOINCGAULQ-QFMPWRQOSA-N
• PubChem CID: 135421339

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

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [2]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: BRAF kinase assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of SB590885 by aberration of the drug's therapeutic target

Colon cancer [ICD-11: 2B90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Collagen triple helix repeat-containing protein 1 (CTHRC1) [1]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Mutations; Arg622Ile
• Experiment for Molecule Alteration: qRT-PCR; Immune cells infiltrating assay
• Experiment for Drug Resistance: Immunohistochemistry assay; Pearson correlation testing
• Mechanism Description: Colon cancer, thyroid cancer, and melanoma are common malignant tumors that seriously threaten human health globally. The B-Raf proto-oncogene, serine/threonine kinase (BRAF)(V600E) mutation is an important driver gene mutation in these cancer types. In this study, we identified that collagen triple helix repeat containing 1 (CTHRC1) expression was associated with the BRAF(V600E) mutation in colon cancer, thyroid cancer, and melanoma. A high level of CTHRC1 was correlated with decreased sensitivity to antitumor drugs (vemurafenib, PLX-4720, dabrafenib, and SB-590885) targeting the BRAF(V600E) mutation.

Melanoma [ICD-11: 2C30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.55 Å; PDB: 4E26
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 3.20 Å; PDB: 4G9R

RMSD: 1.53; TM score: 0.95765; Amino acid change: V600E

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vitro Model: 8505C cells; Thyroid; Homo sapiens (Human); CVCL_1054
• In Vitro Model: Hth104 cells; Thyroid gland; Homo sapiens (Human); CVCL_A427
• In Vivo Model: Mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of SB590885 by aberration of the drug's therapeutic target

References

• Ref 1: CTHRC1 is associated with BRAF(V600E) mutation and correlates with prognosis, immune cell infiltration, and drug resistance in colon cancer, thyroid cancer, and melanoma. Biomol Biomed. 2024 Dec 11;25(1):42-61.
• Ref 2: Gatekeeper mutations mediate resistance to BRAF-targeted therapiesSci Transl Med. 2010 Jun 9;2(35):35ra41. doi: 10.1126/scitranslmed.3000758.
• Ref 3: An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF SignalingCancer Cell. 2016 Sep 12;30(3):485-498. doi: 10.1016/j.ccell.2016.06.024. Epub 2016 Aug 11.