PHA-739358 (Danusertib) is a small molecule with low nanomolar activity against all aurora kinases (AKs) with IC50 value of 13 nM for aurora-A and 79 nM for aurora-B respectively. PHA-739358 (Danusertib) also inhibits other cancer relevant tyrosine kinases such as wild type and mutated ABL, RET, TRK-A and FGFRs.
|Cell lines||wild-type (HCT-116 cells )or p53 −/− MEF (A2780) cells|
|Preparation method||Analysis of Cell Proliferation Analysis was done as previously described (20). Briefly, cells were seeded at different densities in 24-well plates with the appropriate medium. After 24 h, cells were treated with compound and incubated for 72 h at 37°C in 5% CO2 atmosphere. At the end of the incubation time, cells were detached from each plate and counted using a cell counter (Coulter Counter-Beckman). IC50 values were calculated using percent of growth versus untreated control.|
|Incubation time||24 or 48 hr|
|Animal models||Mice bearing established A2780 and HCT-116 tumor xenografts|
|Dosages||30 mg/kg bd for 5 consecutive 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 ≥95 mg/mL|
|Source||PLoS One (2014). Figure 1. PHA-739358|
|Cell Lines||Ba/F3 cells|
|Incubation Time||48 h|
|Results||Accordingly, IC50 values were in a range of 150 nM for PHA-739358 and 10 nM for R763/AS703569, independent of the BCR-ABL mutation status|
Targeting Aurora Kinases with Danusertib (PHA-739358) Inhibits Growth of Liver Metastases from Gastroenteropancreatic Neuroendocrine Tumors in an Orthotopic Xenograft Model.
Fraedrich K, et al. Clin Cancer Res. 2012 Sep 1;18(17):4621-32. PMID: 22753592.
Treatment of human pre-B acute lymphoblastic leukemia with the Aurora kinase inhibitor PHA-739358 (Danusertib).
Fei F, et al. Mol Cancer. 2012 Jun 21;11(1):42. PMID: 22721004.
Danusertib, an aurora kinase inhibitor.
Meulenbeld HJ, et al. Expert Opin Investig Drugs. 2012 Mar;21(3):383-93. PMID: 22242557.
The molecular mechanism studies of chirality effect of PHA-739358 on Aurora kinase A by molecular dynamics simulation and free energy calculations.
Cheng Y, et al. J Comput Aided Mol Des. 2011 Feb;25(2):171-80. PMID: 21222017.
Danusertib (formerly PHA-739358)--a novel combined pan-Aurora kinases and third generation Bcr-Abl tyrosine kinase inhibitor.
Gontarewicz A, et al. Recent Results Cancer Res. 2010;184:199-214. PMID: 20072840.
PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer.
Carpinelli P, et al. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3158-68. PMID: 18089710.
|Related Aurora Kinase Products|
SNS-314 is a potent and selective inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 9 nM, 31 nM, and 3 nM, respectively.
GSK1070916 is a reversible and ATP-competitive inhibitor of Aurora B/C with IC50 of 3.5 nM/6.5 nM. It displays >100-fold selectivity against the closely related Aurora A-TPX2 complex.
PHA-680632 is potent inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 27 nM, 135 nM and 120 nM, respectively. It has 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, and VEGFR2/3.
MK-5108 (VX-689) is a highly selective Aurora A inhibitor with IC50 of 0.064 nM and is 220- and 190-fold more selective for Aurora A than Aurora B/C, while it inhibits TrkA with less than 100-fold selectivity.
PF-03814735 is a novel, potent and reversible inhibitor of Aurora A/B with IC50of 0.8 nM/5 nM, is less potent to Flt3, FAK, TrkA, and minimally active to Met and FGFR1.
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