CUDC-907

Biological Activity

CUDC-907 is an orally-available small molecule inhibitor that targets both HDAC and PI3K with IC50 values of 19 nM, 54 nM, 311 nM and 39 nM for PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ respectively. CUDC-907 potently inhibits class I PI3Ks as well as classes I and II HDAC enzymes. CUDC-907 durably inhibits the PI3K-AKT-mTOR pathway and compensatory signaling molecules such as RAF, MEK, MAPK, and STAT-3, as well as upstream receptor tyrosine kinases. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells. CUDC-907 is currently in phase I clinical trials for patients with solid tumors or lymphoma.

Customer Product Validations & Biological Datas

	Source	Stem Cells Dev (2017). Figure 3. CUDC-907
	Method	Western blot
	Cell Lines	H3K9ac, H4K8ac, H3K4me2 cell
	Concentrations	500 nM
	Incubation Time	24 h
	Results	Interestingly, the combination of both HDAC and PI3K inhibitors failed to induce adipogenesis, suggesting additional possible mechanism by which CUDC-907 promotes adipogenesis

	Source	Stem Cells Dev (2017). Figure 1. CUDC-907
	Method	Adipogenic differentiation
	Cell Lines	hMSCs
	Concentrations	500 nM
	Incubation Time	24 h
	Results	CUDC-907 treatment of hBMSCs enhanced adipocyte differentiation, as evidenced by the greater Oil Red O staining and quantitative analysis demonstrated that the number of mature adipocytes identified by Nile red staining was higher.

Protocol

Cell Experiment
Cell lines	BT474, N87, H1975, H1993, Calu-6, H460 cells line
Preparation method	Cancer cell growth inhibition assay Human cancer cell lines were purchased from American Type Culture Collection (Manassas, VA) and plated at densities of 5,000 to 10,000 per well in 96-well flat-bottomed plates with the recommended culture medium. The cells were then incubated with compounds at various concentrations for 72 hours in culture medium supplemented with 0.5% (v/v) FBS. Growth inhibition was assessed by assay of cellular ATP content using the Perkin-Elmer ATPlite kit.
Concentrations	0~900nM
Incubation time	72 h

Animal Experiment
Animal models	Six- to 8-week-old female athymic (nude nu/nu CD-1) or severe combined immunodeficient (SCID) mice Daudi NHL xenograft mouse model
Formulation	formulated in 30% Captisol
Dosages	25, 50, and 100 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

Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling.
Qian C, et al. Clin Cancer Res. 2012 Aug 1;18(15):4104-13. PMID: 22693356.