SAR245409

mTOR/PI3K inhibitor CAS# 934493-76-2

SAR245409

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Quality Control of SAR245409

3D structure

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SAR245409

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Chemical Properties of SAR245409

Cas No. 934493-76-2 SDF Download SDF
PubChem ID 16123056 Appearance Powder
Formula C13H14N6O M.Wt 270.3
Type of Compound N/A Storage Desiccate at -20°C
Synonyms voxtalisib
Solubility DMSO : 10 mg/mL (37.00 mM; Need ultrasonic)
Chemical Name 2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7-one
SMILES CCN1C2=NC(=NC(=C2C=C(C1=O)C3=CC=NN3)C)N
Standard InChIKey RGHYDLZMTYDBDT-UHFFFAOYSA-N
Standard InChI InChI=1S/C13H14N6O/c1-3-19-11-8(7(2)16-13(14)17-11)6-9(12(19)20)10-4-5-15-18-10/h4-6H,3H2,1-2H3,(H,15,18)(H2,14,16,17)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of SAR245409

DescriptionSAR245409 is a dual inhibitor of mTOR/PI3K.
TargetsPI3KγPI3KαPI3KδPI3KβDNA-PKmTOR
IC509 nM39 nM43 nM113 nM150 nM157 nM

SAR245409 Dilution Calculator

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SAR245409 Molarity Calculator

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Preparing Stock Solutions of SAR245409

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.6996 mL 18.498 mL 36.9959 mL 73.9919 mL 92.4898 mL
5 mM 0.7399 mL 3.6996 mL 7.3992 mL 14.7984 mL 18.498 mL
10 mM 0.37 mL 1.8498 mL 3.6996 mL 7.3992 mL 9.249 mL
50 mM 0.074 mL 0.37 mL 0.7399 mL 1.4798 mL 1.8498 mL
100 mM 0.037 mL 0.185 mL 0.37 mL 0.7399 mL 0.9249 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Organizitions Citing Our Products recently

 
 
 

Calcutta University

University of Minnesota

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Universidade da Beira Interior

The Institute of Cancer Research

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DRURY University
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Jilin University
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Universite de Paris
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Auckland University
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The University of Tokyo
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Korea University
Korea University

Background on SAR245409

SAR245409 (XL765) is a selective dual inhibitor of PI3K and mTOR (IC50= 9 nM for PI3Kγ).

PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) is a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. It plays a key role in PI3K/Akt/mTOR pathway.

In PA cell lines, combination of XL765 and TMZ blocked the cell growth and led to apoptosis [1]. In a variety of tumor cell lines that mutated on PI3K signaling, XL765 inhibited PIP3 formation in the membrane and AKT/p70S6K/S6 phosphorylation [2].

In GH3 xenograft tumor mouse models, combination use of XL765 and TMZ inhibited tumor growth, reduced serum GH and prolactin levels with no increased systemic side effects [1]. In severe combined immunodeficient mice, XL765 abolished MPNST local and metastatic growth. [3]. In multiple human xenograft models in nude mice, repeat dose administration showed significant tumor growth inhibition that related to antiproliferative and antiangiogenic response etc. [2]

References:
1.  Dai C, Zhang B, Liu X et al. Inhibition of PI3K/AKT/mTOR pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice. Endocrinology. 2013 Mar;154(3):1247-59.
2.  Yu P, Laird AD, Du X et al. Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathway. Mol
Cancer Ther.  2014 May;13(5):1078-91.
3.  Ghadimi MP, Lopez G, Torres KE et al. Targeting the PI3K/mTOR axis, alone and in combination with autophagy blockade, for the treatment of malignant peripheral nerve sheath tumors. Mol Cancer Ther. 2012 Aug;11(8):1758-69.

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References on SAR245409

Dual PI3K/mTOR inhibitor, XL765 (SAR245409), shows superior effects to sole PI3K [XL147 (SAR245408)] or mTOR [rapamycin] inhibition in prostate cancer cell models.[Pubmed:26219891]

Tumour Biol. 2016 Jan;37(1):341-51.

Deregulation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway contributes to prostate cancer development and progression. Here, we compared the in vitro effects of the dual PI3K/mTOR inhibitor (XL765) with those observed with the sole PI3K (XL147) or mTOR (rapamycin) inhibition in 2 non-tumor prostate epithelial cell lines, 8 prostate cancer cell lines, and 11 prostate cancer cell derivatives. We demonstrated that the XL765 treatment showed superior and proliferative effects of XL147 or rapamycin. The XL765 effects were associated to increasing the chromosome region maintenance 1 (CRM1)-mediated nuclear localization of glycogen synthase kinase 3 beta (GSK3beta) and Foxo-1a with higher induction of apoptosis when compared to those observed in XL147 and rapamycin treatments. IC50 values were calculated in phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-positive and PTEN-negative cell lines as well as after PTEN transfection or PTEN downmodulation by siRNA strategy revealing that the presence of this protein was associated with reduced sensitivity to PI3K and mTOR inhibitors. The comparison of IC50 values was also calculated for androgen-dependent and -independent cell lines as well as after androgen receptor (AR) transfection or the AR downmodulation by siRNA strategy revealing that androgen independence was associated with enhanced responsiveness. Our results provide a rationale to use the dual PI3K/Akt/mTOR inhibitors in hormone-insensitive prostate cancer models due to the overactivity of PI3K/Akt/mTOR in this disease condition.

The pan phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) blocks survival, adhesion and proliferation of primary chronic lymphocytic leukemia cells.[Pubmed:26338274]

Leukemia. 2016 Feb;30(2):337-45.

The phosphoinositide 3-kinases (PI3Ks) are critical components of the B-cell receptor (BCR) pathway and have an important role in the pathobiology of chronic lymphocytic leukemia (CLL). Inhibitors of PI3Kdelta block BCR-mediated cross-talk between CLL cells and the lymph node microenvironment and provide significant clinical benefit to CLL patients. However, the PI3Kdelta inhibitors applied thus far have limited direct impact on leukemia cell survival and thus are unlikely to eradicate the disease. The use of inhibitors of multiple isoforms of PI3K might lead to deeper remissions. Here we demonstrate that the pan-PI3K/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) was more pro-apoptotic to CLL cells--irrespective of their ATM/p53 status--than PI3Kalpha or PI3Kdelta isoform selective inhibitors. Furthermore, SAR245409 blocked CLL survival, adhesion and proliferation. Moreover, SAR245409 was a more potent inhibitor of T-cell-mediated production of cytokines, which support CLL survival. Taken together, our in vitro data provide a rationale for the evaluation of a pan-PI3K inhibitor in CLL patients.

Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma.[Pubmed:26019185]

Neuro Oncol. 2015 Sep;17(9):1275-83.

BACKGROUND: This phase I study aimed to evaluate safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics, and preliminary efficacy of voxtalisib (SAR245409, XL765), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, in combination with temozolomide (TMZ), with or without radiation therapy (RT), in patients with high-grade glioma. METHODS: Patients received voxtalisib 30-90 mg once daily (q.d.) or 20-50 mg twice daily (b.i.d.), in combination with 200 mg/m(2) TMZ (n = 49), or voxtalisib 20 mg q.d. with 75 mg/m(2) TMZ and RT (n = 5). A standard 3 + 3 dose-escalation design was used to determine the maximum tolerated dose. Patients were evaluated for adverse events (AEs), plasma pharmacokinetics, pharmacodynamic effects in skin biopsies, and tumor response. RESULTS: The maximum tolerated doses were 90 mg q.d. and 40 mg b.i.d. for voxtalisib in combination with TMZ. The most frequently reported treatment-related AEs were nausea (48%), fatigue (43%), thrombocytopenia (26%), and diarrhea (24%). The most frequently reported treatment-related grade >/=3 AEs were lymphopenia (13%), thrombocytopenia, and decreased platelet count (9% each). Pharmacokinetic parameters were similar to previous studies with voxtalisib monotherapy. Moderate inhibition of PI3K signaling was observed in skin biopsies. Best response was partial response in 4% of evaluable patients, with stable disease observed in 68%. CONCLUSIONS: Voxtalisib in combination with TMZ with or without RT in patients with high-grade gliomas demonstrated a favorable safety profile and a moderate level of PI3K/mTOR pathway inhibition.

Description

Voxtalisib (XL765) is a potent PI3K inhibitor, which has a similar activity toward class I PI3K (IC50s=39, 113, 9 and 43 nM for p110α, p110β, p110γ and p110δ, respectively), also inhibits DNA-PK (IC50=150 nM) and mTOR (IC50=157 nM). Voxtalisib (XL765) inhibits mTORC1 and mTORC2 with IC50s of 160 and 910 nM, respectively.

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