HLM006474 Chemical Properties

Boiling point:

588.7±50.0 °C(Predicted)

Density 

1.227±0.06 g/cm3(Predicted)

storage temp. 

2-8°C

solubility 

DMSO:25.0(Max Conc. mg/mL);62.58(Max Conc. mM)

form 

Off-white solid

pka

4.36±0.50(Predicted)

color 

White to off-white

InChI

1S/C25H25N3O2/c1-4-30-21-13-11-19(15-16(21)2)23(28-22-7-5-6-14-26-22)20-12-10-18-9-8-17(3)27-24(18)25(20)29/h5-15,23,29H,4H2,1-3H3,(H,26,28)

InChIKey

CYNZBLNMIJNBSF-UHFFFAOYSA-N

SMILES

CC1=CC(C(NC2=NC=CC=C2)C3=C(O)C(N=C(C)C=C4)=C4C=C3)=CC=C1OCC

Safety Information

WGK Germany 

WGK 3

Storage Class

11 - Combustible Solids

HLM006474 Usage And Synthesis

Description

HLM006474 is a non-selective inhibitor of the transcription factor E2F (IC₅₀ = 29.8 μM for E2F4). It inhibits DNA binding to E2F1, E2F2, and E2F4 in A375 melanoma cells when used at a concentration of 40 μM. HLM006474 (40 μM) decreases protein levels of E2F4 and cyclin D3 and induces apoptosis in A375 cells. It also induces apoptosis in MDA-MB-231, but not MCF-7, cells and inhibits the growth of cancer cells in a panel of 17 lung cancer cell lines (IC₅₀s = 15.5-75.1 μM). HLM006474 reduces tumor growth in retinoblastoma-prone Chx10Cre;Rb^fl/fl;p107^-/- mice and in an A375 mouse xenograft model when administered at a dose of 100 mg/kg and 2 mg per mouse, respectively.

Uses

HLM006474 has been used as an E2 factor?(E2F) inhibitor in human nasopharyngeal carcinoma hone-1 cells and T. annulata-infected TBL20 cells.

Uses

HLM 006474 acts as an E2F transcription factor inhibitor, preventing DNA binding activity. This results in the induction of apoptosis in breast cancer cells.

General Description

A cell-permeable 8-hydroxyquinoline compound that is reported to inhibit nuclear E2F complexes DNA binding activity (IC₅₀ = 30 μM) and downregulate E2F expression in the melanoma cell line A375, resulting in eventual apoptosis induction without upregulating p53 expression as commonly seen with traditional chemotherapeutic agents, such as Cisplatin (Cat. No. 232120), doxorubicin (Cat. No. 324380), and VP-16 (Cat. No. 341205).

Biochem/physiol Actions

HLM006474 is a pan-E2F transcription factor inhibitor. E2F s part of the CDK/Rb/E2F pathway. When phosphorylated by CDKs, the tumor suppressor retinoblastoma protein (Rb) is inactivated, releasing E2Fs and allowing cell cycle progression. HLM006474 inhibited DNA-binding of all E2F complexes and down-regulated expression of E2F4 protein. HLM006474 induced apoptosis of A375 melanoma cells and synergized with paclitaxel in lung cancer cell lines.

References

[1] YIHONG MA. A small-molecule E2F inhibitor blocks growth in a melanoma culture model.[J]. Cancer research, 2008: 6292-6299. DOI: 10.1158/0008-5472.can-08-0121
[2] COURTNEY A KURTYKA  W D C  Lu Chen. E2F inhibition synergizes with paclitaxel in lung cancer cell lines.[J]. PLoS ONE, 2014: e96357. DOI: 10.1371/journal.pone.0096357
[3] M SANGWAN. Established and new mouse models reveal E2f1 and Cdk2 dependency of retinoblastoma, and expose effective strategies to block tumor initiation[J]. Oncogene, 2012, 31 48: 5019-5028. DOI: 10.1038/onc.2011.654
[4] FLORIAN ROUAUD. E2F1 inhibition mediates cell death of metastatic melanoma.[J]. Cell Death & Disease, 2018: 527. DOI: 10.1038/s41419-018-0566-1