SAR405 is a low-molecular-mass kinase inhibitor of Vps34 (KD 1.5 nM). SAR405 has an exquisite protein and lipid kinase selectivity profile that is explained by its unique binding mode and molecular interactions within the ATP binding cleft of human Vps34. Inhibition of Vps34 kinase activity by SAR405 affects both late endosome-lysosome compartments and prevents autophagy. SAR405 shows a binding equilibrium constant KD of 1.52±0.77 nM (±s.d.) and a dissociation rate constant, koff, of 3.03 ± 0.55 10-3 s-1, corresponding to a residence half-life, t1/2, of 3.8 min. The activity of SAR405 is next evaluated on a dedicated Vps34 cellular assay using a GFP-FYVE–transfected HeLa cell line. SAR405 is a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells. SAR405 is a proximal inhibitor of the autophagy machinery. SAR405 prevents autophagosome formation with an IC50 of 42 nM. Treatment of starved cells with SAR405 completely inhibits the conversion to LC3-II in a dose-dependent manner. The effect of SAR405 on autophagy is then investigated. The GFP-LC3 model is used for the HTS and confirmed its activity on starved cells (IC50=419 nM). The conversion of LC3-I into LC3-II is also analyzed by western blotting on wild-type HeLa and H1299 cells.
|Cell lines||RT-112 cells|
|Preparation method||All cell lines were cultured in Dulbecco’s Modified Eagle Medium (DMEM) containing 10% FCS and 4.5 g/l D-glucose in a humidified atmosphere at 37°C and 5% CO2. The Cisplatin-resistant sublines were generated over several months by increasing dosages of cisplatin added with every passage up to concentrations of 12, 1, 2, 7, 3.5, or 1.5 µg/ml to RT-112, J82, 253J, T24, 5637, and SW-1710 cells, respectively.|
|Incubation time||72 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||27 mg/mL in DMSO|
Targeting urothelial carcinoma cells by combining cisplatin with a specific inhibitor of the autophagy-inducing class III PtdIns3K complex.
Schlütermann D, et al. Urol Oncol. 2018 Apr;36(4):160. PMID: 29276062.
Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target.
New J, et al. Cancer Res. 2017 Dec 1;77(23):6679-6691. PMID: 28972076.
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