CX-6258 inhibited Flt-3 and Pim-3 (IC50=0.134 and 0.016 uM). CX-6258 is a reversible inhibitor of Pim-1 (Ki=0.005 uM). CX-6258 shows robust antiproliferative potencies against all cell lines tested derived from human solid tumors and hematological malignancies. CX-6258 shows dose-dependent efficacy in mice bearing MV-4-11 xenografts, with 45% and 75% TGI at 50 and 100 mg/kg/day, respectively.
|Source||Clin Cancer Res (2016). Figure 3. CX-6258|
|Cell Lines||PC3 and DU145 cells|
|Concentrations||0, 5, or 10 mmol/L|
|Results||Cell-cycle analyses of LNCaP cells 48 hours following CX- 6258 treatment revealed a significant decrease in G0–G1 phase and a pronounced accumulation of cells in G2–M phase|
|Cell lines||MV-4-11, SEM, EOL-1, MOLM-13, PL-21, THP-1, K562, MEG01, HL60 and U266 cells|
|Preparation method||Cell Viability assay.
For proliferation assays, cells were plated at 5,000 to 20,000 cells per well in 96 well plates overnight before treatment for 96 hours with serially diluted compound or vehicle DMSO. Cell viability was measured after the addition of 10 μL Alamar Blue (Invitrogen) for 4 hours at 37˚C. The GI50 was determined by calculating growth at each dose relative to vehicle treated cells and cell viability at the time of treatment.
|Incubation time||96 h|
|Animal models||MV-4-11 xenograft models in nude mice|
|Dosages||50 or 100 mg/kg once daily over a period of 21 days|
|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||DMSO 10 mM|
Discovery of CX-6258. A Potent, Selective, and Orally Efficacious pan-Pim Kinases Inhibitor.
Haddach M, et al. ACS Med Chem Lett. 2011 Dec 27;3(2):135-9. PMID: 24900437.
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CX-6258 HCl is a potent, orally efficacious pan-Pim kinase inhibitor with IC50 of 5 nM, 25 nM and 16 nM for Pim1, Pim2, and Pim3, respectively.
TCS-PIM-1-4a is a Pim inhibitor that blocks mTORC1 activity via activation of AMPK; kills a wide range of both myeloid and lymphoid cell lines (with IC50 values ranging from 0.8 to 40 μM).
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|TCS PIM-1 1
TCS PIM-1 1 is a potent and selective ATP-competitive Pim-1 kianse inhibitor with IC50 of 50 nM, displays good selectivity over Pim-2 and MEK1/MEK2(IC50s > 20,000 nM).
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