Drug Information

Drug (ID: DG01868) and It's Reported Resistant Information

• Name: NS1
• Synonyms: NS1
• Indication:
  In total 1 Indication(s)
  Hyperlipidaemia [ICD-11: 5C80]; Approved; [1]
• Target: .; NOUNIPROTAC; [1]

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

Bladder cancer [ICD-11: 2C94]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Hras (HRAS) [1]

• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Ras signaling pathway; Inhibition; hsa04014
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: COS cells; N.A.; .; N.A.
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: NS1, that bound with high affinity to both GTP- and GDP-bound states of H- and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H- and K-RAS-mediated signaling and transformation but did not block oncogenic N-RAS, BRAF or MEK1. NS1 bound the alpha4-beta6-alpha5 region of RAS disrupting RAS dimerization/nanoclustering, which in turn blocked CRAF:BRAF heterodimerization and activation. These results establish the importance of the alpha4-beta6-alpha5 interface in RAS-mediated signaling and define a previously unrecognized site in RAS for inhibiting RAS function.

References

• Ref 1: Inhibition of RAS function through targeting an allosteric regulatory siteNat Chem Biol. 2017 Jan;13(1):62-68. doi: 10.1038/nchembio.2231. Epub 2016 Nov 7.