XL147 analogue

Catalog No.S1118 Synonyms: SAR245408

XL147 analogue Chemical Structure

Molecular Weight(MW): 448.52

XL147 analogue is a selective and reversible class I PI3K inhibitor for PI3Kα/δ/γ with IC50 of 39 nM/36 nM/23 nM in cell-free assays, less potent to PI3Kβ. Phase 1/2.

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2 Customer Reviews

  • Breast cancer cells were pretreated with 100ng/ml EGF for 20 min and then treated with the indicated concentrations of XL147 for 24 hours.

    XL147 analogue purchased from Selleck.

    Western blot analysis of Akt and p-Akt. 0-15μM XL-147 was added.

    Dr. Chunrong Yu of RoswelI Park Cancer Institute. XL147 analogue purchased from Selleck.

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Biological Activity

Description XL147 analogue is a selective and reversible class I PI3K inhibitor for PI3Kα/δ/γ with IC50 of 39 nM/36 nM/23 nM in cell-free assays, less potent to PI3Kβ. Phase 1/2.
Targets
PI3Kγ [1]
(Cell-free assay)
PI3Kδ [1]
(Cell-free assay)
PI3Kα [1]
(Cell-free assay)
PI3Kβ [1]
(Cell-free assay)
DNA-PK [1]
(Cell-free assay)
23 nM 36 nM 39 nM 383 nM 4.75 μM
In vitro

XL147 inhibits class I PI3K isoforms in an ATP-competitive manner. In a panel of HER2-overexpressing human breast cancer cell lines, treatment with XL147 abrogates AKT and S6 phosphorylation but also induces the expression and phosphorylation of HER3 and other RTKs. In HER2+ cells, phosphorylation of HER3 is maintained by the HER2 tyrosine kinase, leading to partial recovery of phosphorylated AKT (pAKT) and thereby limiting the antitumor action of XL 147. In addition, knockdown of HER3 or treatment with the anti-HER2 agents trastuzumab or lapatinib sensitizes HER2+ breast cancer cells to XL147 in vitro and in vivo. Treatment with XL147 inhibits the monolayer growth of all tested cell lines, including BT474, HCC1937 et al. in a dose-dependent manner. The main effect of XL147 is inhibition of cell proliferation. XL147 induces cell death at the concentration of 20 μM. Treatment with XL147 leads to dose-dependent inhibition of PI3K. Consistent with the inhibition of cell proliferation, XL147 induces a reduction in cyclin D1 and pRB and an increase in levels of the CDK inhibitor p27KIPI but no detectable change in levels off total or cleaved poly (ADP-ribose) polymerase (PARP). Treatment with XL147 leads to a dose-dependent reduction in pAKTS473/T308 and pS6S240/244. Surprisingly, XL147 also triggers up-regulation of total HER3 and/or pHER3Y1289 levels. In HER2-overexpressing cells, inhibition of PI3K is followed by up-regulation of expression and phosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3a transcription factors prevents the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition of PI3K. In HER2+ cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhances XL147-induced cell death and inhibition of pAKT and pS6. [2]

In vivo Athymic mice with BT474 xenografts are randomly treated with XL147, lapatinib, trastuzumab, or XL147 plus each HER2 antagonist. Each monotherapy significantly inhibtis tumor growth with trastuzumab being the only agent that induced a complete tumor regression in one of eight mice. Both combinations are superior to the respective drugs given alone. Notably, the combination of trastuzumab and XL147, but not lapatinib and XL147, induces a complete tumor response in three of eight mice. There is no marked drug-related toxicity in any of the treatment arms. The combination of XL147 plus trastuzumab prevents pHER3 more potently than any of the other treatments. In good agreement with differences in tumor growth among treatment arms, nuclear pAKT is lower in tumors treated with XL147 plus lapatinib or XL147 plus trastuzumab compared with tumors treated with single agents. Of all three single drugs, XL147 is the only one shown statistically to repress nuclear pAKT levels. There are no detectable changes in cytoplasmic pAKT levels. Combined inhibition of HER2 and PI3K in HER2-dependent xenografts is required to maximally inhibit signaling output of the PI3K/AKT pathway. [2]

Protocol

Cell Research:

[2]

+ Expand
  • Cell lines: BT474 and HCC1937 cells
  • Concentrations: 0-20 μM
  • Incubation Time: 72 hours
  • Method:

    Cells including BT474, HCC1937 et al. are seeded in 100-mm dishes in media containing 2.5% FBS with or without XL147. After 3 days, detached and adherent cells are pooled, fixed, and labeled with propidium iodide by using the APO-BrdU kit. Labeled cells are analyzed using the Becton Dickinson FACSCalibur system.


    (Only for Reference)
Animal Research:

[2]

+ Expand
  • Animal Models: Athymic female mouse bearing BT474 cells
  • Formulation: Formulated in 10 mM HCl, in sterile water for injection
  • Dosages: 100 mg/kg
  • Administration: Orogastric gavage
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 3 mg/mL (6.68 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 15 mg/mL

* 1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 448.52
Formula

C21H16N6O2S2

CAS No. 956958-53-5
Storage powder
in solvent
Synonyms SAR245408

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01943838 Completed Neoplasm Malignant Sanofi October 2013 Phase 1
NCT01587040 Active, not recruiting Neoplasm Malignant Sanofi July 2012 Phase 1|Phase 2
NCT01436565 Completed Solid Tumor Cancers Sanofi|Merrimack Pharmaceuticals November 2011 Phase 1
NCT01392924 Completed Neoplasm Malignant Sanofi August 2011 Phase 1
NCT01357330 Completed Solid Tumors Sanofi May 2011 Phase 1
NCT01240460 Completed Glioblastoma|Astrocytoma, Grade IV Sanofi January 2011 Phase 1

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID