HPI-4

• Catalog No.: H4541
• CAS Number: 302803-72-1
• M. F.: C17H9Cl2N3O2
• M. W.: 358.17826
• Purity: ≥98% (HPLC)

SYNONYMS

• IUPAC name: 3-(2,4-dichlorophenyl)-3-oxo-2-(4-oxo-1,2,3,4-tetrahydroquinazolin-2-ylidene)propanenitrile
• IUPAC Traditional name: 3-(2,4-dichlorophenyl)-3-oxo-2-(4-oxo-1,3-dihydroquinazolin-2-ylidene)propanenitrile
• Synonyms: Ciliobrevin A; Hedgehog Pathway Inhibitor 4; 2,4-Dichloro-a-(3,4-dihydro-4-oxo-2(1H)-quinazolinylidene)-β-oxo-benzenepropanenitrile

DATABASE IDS

• CAS Number: 302803-72-1
• MDL Number: MFCD01911757

PROPERTIES

• Empirical Formula (Hill Notation): C17H9Cl2N3O2
• Purity: ≥98% (HPLC)
• Apperance: yellow powder
• Solubility: DMSO: >20 mg/mL
• GHS Signal Word: Warning
• GHS Hazard statements: H302-H410
• European Hazard Symbols: Harmful (Xn)
• European Hazard Symbols: Nature polluting (N)
• GHS Precautionary statements: P273-P501
• RID/ADR: UN 3077 9/PG 3
• Risk Statements: 22-50/53
• Safety Statements: 60-61
• Storage Temperature: 2-8°C
• Hazard Class: 9
• UN Number: 3077
• Packing Group: 3
• German water hazard class: 3

DETAILS

Description (简体中文)

Biochem/physiol Actions
HPI-4 is a Hedgehog pathway inhibitor; ciliogenesis inhibitor. The Hedgehog (HH) signaling pathway is targeted for anti-cancer therapeutics. A key signaling molecule in HH pathway, Smoothened (Smo), has been the target of pharmacological intervention, which has resulted in multiple Smo antagonists including Cyclopamine. However, the oncogenic form of Smo is resistant to Cyclopamine, so the identification of inhibitors of downstream effectors, such as the transcription factors Gli1 and Gli2, is important. Four small molecules were identified to inhibit HH downstream of Smo, HPI-1, HPI-2, HPI-3, and HPI-4. HPI-4 blocked HH pathway activation by SAG, decreased Smo ciliary accumulation, decreased HH activity in a consitutively active HH cell line, and decreased Gli1 and Gli2, processing, and stability. HPI-4 inhibited proliferation of cerebellar granula neuron precursor cells, an important model of HH signaling. Cilia in HPI-4-treated cells were either truncated or absent. The mechanism of action of HPI-4 is hypothesized to be directly through perturbation of ciliogenesis, leading to disruption of Gli1/Gli2 activity, which is distinctly different from that of Cyclopamine.

Description (English)

Biochem/physiol Actions
HPI-4 is a Hedgehog pathway inhibitor; ciliogenesis inhibitor. The Hedgehog (HH) signaling pathway is targeted for anti-cancer therapeutics. A key signaling molecule in HH pathway, Smoothened (Smo), has been the target of pharmacological intervention, which has resulted in multiple Smo antagonists including Cyclopamine. However, the oncogenic form of Smo is resistant to Cyclopamine, so the identification of inhibitors of downstream effectors, such as the transcription factors Gli1 and Gli2, is important. Four small molecules were identified to inhibit HH downstream of Smo, HPI-1, HPI-2, HPI-3, and HPI-4. HPI-4 blocked HH pathway activation by SAG, decreased Smo ciliary accumulation, decreased HH activity in a consitutively active HH cell line, and decreased Gli1 and Gli2, processing, and stability. HPI-4 inhibited proliferation of cerebellar granula neuron precursor cells, an important model of HH signaling. Cilia in HPI-4-treated cells were either truncated or absent. The mechanism of action of HPI-4 is hypothesized to be directly through perturbation of ciliogenesis, leading to disruption of Gli1/Gli2 activity, which is distinctly different from that of Cyclopamine.