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.
|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.|
|Incubation time||72 h|
|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|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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 Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
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.
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TMP195 is a selective, first-in-class, class IIa HDAC inhibitor with IC50 of 300 nM in cell-based class IIa HDAC assays.
WT-161 is a potent and selective HDAC6 inhibitor with an IC50 of 0.40 nM.
EDO-S101 is a pan HDAC inhibitor; inhibits HDAC1, HDAC2 and HDAC3 with IC50 values of 9, 9 and 25 nM, respectively.
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