CUDC-305

Biological Activity

CUDC-305 is a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy.CUDC-305 shows high affinity for HSP90α/β (IC50, ～100 nmol/L) and HSP90 complex derived from cancer cells (IC50, 48.8 nmol/L). It displays potent antiproliferative activity against a broad range of cancer cell lines (mean IC50, 220 nmol/L). CUDC-305 exhibits high oral bioavailability (96.0%) and selective retention in tumor (half-life,20.4 hours) compared with normal tissues. Furthermore, CUDC-305 can cross bloodbrain barrier and reach therapeutic levels in brain tissue. CUDC-305 exhibits dosedependent antitumor activity in an s.c. xenograft model of U87MG glioblastoma and significantly prolongs animal survival in U87MG orthotopic model. CUDC-305 also displays potent antitumor activity in animal models of erlotinib-resistant non–small cell lung cancer and induces tumor regression in animal models of MDA-MB-468 breast cancer and MV4-11 acute myelogenous leukemia. Correlating with its efficacy in these various tumor models, CUDC-305 robustly inhibits multiple signaling pathways, including PI3K/AKT and RAF/MEK/ERK, and induces apoptosis. In combination studies, CUDC-305 enhances the antitumor activity of standard-of-care agents in breast and colorectal tumor models.

Product Citations

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  Sci Rep. 2017 Feb 8;7(1):201..

  Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90 inhibition-mediated bladder cancer therapeutics
  CUDC-305 purchased from AbMole

Customer Product Validations & Biological Datas

	Source	Scientific Reports (2017). Figure 1.CUDC305 (AbMole BioScience Houston, TX, USA)
	Method	MTS based assay
	Cell Lines	5637 bladder carcinoma cells
	Concentrations	0, 0.01 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, 1 μM, 10 μM, and 100 μM
	Incubation Time	24, 48, or 72 h.
	Results	These results indicate that these HSP90 inhibitors potently inhibit cell proliferation and induce cell toxicity in bladder cancer 5637 cells.

Protocol

Cell Experiment
Cell lines	BT474, N87, H1975, H1993, Calu-6 and H460 cells line
Preparation method	Cell growth and viability assay. Human cancer cell lines were purchased from American Type Culture Collection and plated at 5,000 to 10,000 per well in 96-well plates with culture medium, as suggested by the provider. The cells were then incubated with compounds at various concentrations for 120 h. Growth inhibition was assessed by ATP content assay using the Perkin-Elmer ATPlite kit. Briefly, a 25-μL cell lysis solution was added to the 50-μL phenol red–free culture medium per well to lyse cells and stabilize ATP. Then 25-μL substrate solutions were added to the wells, and subsequently, luminescence was measured with a TopCount liquid scintillation analyzer (Perkin-Elmer). Values were expressed as a percentage relative to those obtained in untreated controls. IC50 values were calculated using PRISM software (GraphPad Software) with sigmoidal dose-response curve fitting.
Concentrations	0~900nM
Incubation time	120h

Animal Experiment
Animal models	U87MG glioblastoma tumor models
Formulation	formulated in 30% Captisol
Dosages	single 160 mg/kg
Administration	oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

References

Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer.
Bao et al. Mol Cancer Ther. 2009 Dec;8(12):3296-306. PMID: 19952121.

CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy.
Bao et al. Clin Cancer Res. 2009 Jun 15;15(12):4046-57. PMID: 19509149.