Conglobatin

Conglobatin (FW-04-806), a macrolide dilactone, is isolated from the culture of Streptomyces conglobatus. Conglobatin is an orally active Hsp90 inhibitor. Conglobatin can bind to the N-terminal domain of Hsp90 and disrupt Hsp90-Cdc37 complex formation. Conglobatin induces apoptosis in human breast cancer cells and esophageal squamous cell carcinoma cells, and exhibits antitumor activity in vivo[1][2][3].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Metabolic Enzyme/Protease >> HSP

Signaling Pathways >> Cell Cycle/DNA Damage >> HSP

HSP90

Conglobatin (6.25-100 μM; 48 h) markedly inhibits the proliferation of SKBR3 and MCF-7 cells, with IC50s of 12.11 and 39.44 μM, respectively[2]. Conglobatin inhibits cell proliferation in EC109, KYSE70, KYSE450, KYSE150, KYSE180, and KYSE510 cells, with IC50s of 16.43, 15.89, 10.94, 10.50, 10.28, and 9.31 μM, respectively[3]. Conglobatin (10-40 μM; 24 h) displays obvious arrest of SKBR3 and MCF-7 cells in the G2/M phase. Conglobatin induces apoptosis through caspase-dependent pathways in SKBR3 and MCF-7 cells[2]. Conglobatin (10-40 μM; 3-24 h) reduces Hsp90 client protein levels and induces proteasome-dependent degradation[2]. Conglobatin binds to the N-terminal of Hsp90, does not affect ATP-binding capability of Hsp90, but inhibits Hsp90/Cdc37 chaperone/co-chaperone interactions[2]. Cell Proliferation Assay[2] Cell Line: SKBR3 and MCF-7 cells Concentration: 6.25, 12.5, 25, 50, 100 μM Incubation Time: 48 hours Result: Inhibited the proliferation of SKBR3 and MCF-7 cells in a dose-dependent manner. Cell Cycle Analysis[2] Cell Line: SKBR3 and MCF-7 cells Concentration: 10, 20, 40 μM Incubation Time: 24 hours Result: Increased the G2/M cell population and decreased the population in the S and G0/G1 phases. Western Blot Analysis[2] Cell Line: SKBR3 and MCF-7 cells Concentration: 10, 20, 40 μM Incubation Time: 3, 6, 12, 24 hours Result: Decreased the levels of the client proteins HER2, p-HER2, Raf-1, Akt, and p-Akt in a dose and time-dependent manner in SKBR3 cells. Reduced the the levels of the client proteins Raf-1, Akt, and p-Akt in a dose and time-dependent manner in MCF-7 cells.

Conglobatin (50-200 mg/kg; i.g. q3d for 24 d) inhibits the tumor growth of SKBR3 and MCF-7 human breast cancer xenograft models in a dose-dependent manner[2]. Conglobatin (4-8 mg/kg; i.p. daily for 21 days) inhibits tumor growth in EC109 and KYSE510 tumor xenograft models with low toxicity[3] Animal Model: BALB/c (nu/nu) athymic mice with SKBR3 and MCF-7 tumor xenograft[2] Dosage: 50, 100, 200 mg/kg Administration: Oral gavage every 3 days for 24 days Result: Showed inhibition of tumor growth at a rate of 39.1%, 52.7%, and 67.5% in the SKBR3 cell line groups and 27.3%, 39.8%, 54.3% in the MCF-7 cell line groups at the three increasing doses, respectively. Was well tolerated.

[1]. Westley JW, et, al. Conglobatin, a novel macrolide dilactone from Streptomyces conglobatus ATCC 31005. J Antibiot (Tokyo). 1979 Sep;32(9):874-7.

[2]. Huang W, et, al. FW-04-806 inhibits proliferation and induces apoptosis in human breast cancer cells by binding to N-terminus of Hsp90 and disrupting Hsp90-Cdc37 complex formation. Mol Cancer. 2014 Jun 14;13:150.

[3]. Li LY, et, al. Macrolide analog F806 suppresses esophageal squamous cell carcinoma (ESCC) by blocking β1 integrin activation. Oncotarget. 2015 Jun 30;6(18):15940-52.

MOLECULAR FORMULA :

C28-H38-N2-O6

MOLECULAR WEIGHT :

498.68

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

>1 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

JANTAJ Journal of Antibiotics. (Japan Antibiotics Research Assoc., 2-20-8 Kamiosaki, Shinagawa-ku, Tokyo, 141, Japan) V.2-5, 1948-52; V.21- 1968- Volume(issue)/page/year: 32,874,1979

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

>1 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

JANTAJ Journal of Antibiotics. (Japan Antibiotics Research Assoc., 2-20-8 Kamiosaki, Shinagawa-ku, Tokyo, 141, Japan) V.2-5, 1948-52; V.21- 1968- Volume(issue)/page/year: 32,874,1979