In vitro: EDOS101 inhibits HDAC activity in rat peripheral blood mononuclear cells (PBMCs) in a cellular assay by approximately 90% one hour after dosing with 10mg/kg i.v. HDAC inhibition in PBMCs could not be increased with higher doses up to 50mg/kg. EDO-S101 triggers apoptosis and shows strong antitumor activity in HL60 and Daudi cells. Initial in vitro experiments in HL60 cells shows an activation of the intrinsic pathway of apoptosis with cleavage of caspases 3, 9 and PARP and a marked reduction of anti-apoptotic proteins XIAP and Mcl-1. In vivo: Intracellular HDAC inhibition of EDO-S101, which occurs rapidly after dosing is at maximum activity already at the lowest dose of 10mg/kg and lasts for about 12-16 hours. Exposure to EDO-S101 causes a strong DNA repair response evidenced by activation of pH2AX and p53 in tumors taken from mice bearing subcutaneous human Burkitt’s lymphoma. Tumors of BL rapidly shrink or are completely eradicated after i.v. administration of EDO-S101.
|Cell lines||human MM cell lines|
|Preparation method||MM1S cells were incubated for 48 h with increasing doses of EDO-S101, together with IL-6 at 1 nM or IGF-1 at 10 nM, and proliferation of MM cells was assessed by MTT assay.|
|Incubation time||48 h|
|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.
|Solubility||30 mg/mL in DMSO|
Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair.
López-Iglesias AA, et al. J Hematol Oncol. 2017 Jun 20;;10(1):127. PMID: 28633670.
The Alkylating-HDAC Inhibition Fusion Principle: Taking Chemotherapy to the Next Level with the First in Class Molecule EDO-S101.
Mehrling T, et al. Anticancer Agents Med Chem. 2016;16(1):20-8. PMID: 25980817.
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ACY-738 is a potent, selective and orally-bioavailable HDAC6 inhibitor, with an IC50s of 1.7 nM.
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