XL147 analogue

Catalogusnr.S1118 Batch:S111804

Afdrukken

Technische gegevens

Formule

C21H16N6O2S2
Molecuulgewicht 448.52 CAS-nr. 956958-53-5
Oplosbaarheid (25°C)* In vitro DMSO 90 mg/mL (200.65 mM)
Water Insoluble
Ethanol Insoluble
In Vivo (Voeg oplosmiddelen afzonderlijk en in volgorde toe aan het product.)
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
* <1 mg/ml betekent licht oplosbaar of onoplosbaar.
* Houd er rekening mee dat Selleck de oplosbaarheid van alle verbindingen intern test en de werkelijke oplosbaarheid enigszins kan afwijken van gepubliceerde waarden. Dit is normaal en is te wijten aan lichte batch-tot-batch variaties.
* Verzending op kamertemperatuur (Stabiliteitstests tonen aan dat dit product zonder koelmaatregelen kan worden verzonden.)

Voorbereiden van stamoplossingen

Biologische activiteit

Beschrijving XL147 analogue (SAR245408) is een selectieve en reversibele klasse I PI3K-remmer voor PI3Kα/δ/γ met een IC50 van 39 nM/36 nM/23 nM in celvrije assays, en is minder krachtig tegen PI3Kβ. Deze verbinding induceert Apoptosis related. Fase 1/2.
Doelen
PI3Kγ
(Cell-free assay)		 PI3Kδ
(Cell-free assay)		 PI3Kα
(Cell-free assay)		 PI3Kβ
(Cell-free assay)
23 nM 36 nM 39 nM 383 nM
In vitro XL147 analogue inhibits class I PI3K isoforms in an ATP-competitive manner. In a panel of HER2-overexpressing human breast cancer cell lines, treatment with this compound 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 this chemical. In addition, knockdown of HER3 or treatment with the anti-HER2 agents trastuzumab or lapatinib sensitizes HER2+ breast cancer cells to this agent in vitro and in vivo. Treatment with this inhibitor inhibits the monolayer growth of all tested cell lines, including BT474, HCC1937 et al. in a dose-dependent manner. The main effect of this compound is inhibition of cell proliferation. It induces cell death at the concentration of 20 μM. Treatment with this chemical leads to dose-dependent inhibition of PI3K. Consistent with the inhibition of cell proliferation, it 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 this agent leads to a dose-dependent reduction in pAKTS473/T308 and pS6S240/244. Surprisingly, it 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.
In Vivo Athymic mice with BT474 xenografts are randomly treated with XL147 analogue, lapatinib, trastuzumab, or this compound 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 this chemical, 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 this compound 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 this chemical plus trastuzumab compared with tumors treated with single agents. Of all three single drugs, this compound 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.

Protocol (uit referentie)

Celassay:

[2]
  • Cellijnen

    BT474 and HCC1937 cells

  • Concentraties

    0-20 μM

  • Incubatietijd

    72 hours

  • Methode

    Cells including BT474, HCC1937 et al. are seeded in 100-mm dishes in media containing 2.5% FBS with or without this compound. 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.
Dierstudie:

[2]
  • Dierlijke modellen

    Athymic female mouse bearing BT474 cells

  • Doseringen

    100 mg/kg

  • Toediening

    Orogastric gavage

Referenties

  • #
  • https://pubmed.ncbi.nlm.nih.gov/21368164/

Klantproductvalidatie

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

Dr. Zhang of Tianjin Medical University ,

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

, , Dr. Chunrong Yu of RoswelI Park Cancer Institute

Selleck's XL147 analogue Is geciteerd door 18 Publicaties

MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB [ Autophagy, June 15, 2012, 903-914] PubMed: 22576015
MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB [ Autophagy, June 1, 2012, 903-914] PubMed: 22576015
Deciphering Combinations of PI3K/AKT/mTOR Pathway Drugs Augmenting Anti-Angiogenic Efficacy In Vivo [ PLoS One, August 21, 2014, e105280] PubMed: 25144531
Establishment and Characterization of NCC-PMP1-C1: A Novel Patient-Derived Cell Line of Metastatic Pseudomyxoma Peritonei [ J Pers Med, 2022, 12(2)258] PubMed: 35207746
Establishment and characterization of NCC-UPS4-C1: a novel cell line of undifferentiated pleomorphic sarcoma from a patient with Li-Fraumeni syndrome [ Hum Cell, 2022, 10.1007/s13577-022-00671-y] PubMed: 35118583
Establishment and Characterization of NCC-PMP1-C1: A Novel Patient-Derived Cell Line of Metastatic Pseudomyxoma Peritonei [ Journal of Personalized Medicine, 2022, 258] PubMed: 35207746
Establishment and characterization of novel patient-derived cell lines from giant cell tumor of bone [ Hum Cell, 2021, 10.1007/s13577-021-00579-z] PubMed: 34304386
Establishment and characterization of the NCC-GCTB4-C1 cell line: a novel patient-derived cell line from giant cell tumor of bone [ Hum Cell, 2021, 10.1007/s13577-021-00639-4] PubMed: 34731453
Establishment and characterization of NCC-MFS4-C1: a novel patient-derived cell line of myxofibrosarcoma [ Hum Cell, 2021, 34(6):1911-1918] PubMed: 34383271
Establishment and characterization of NCC-MFS2-C1: a novel patient-derived cancer cell line of myxofibrosarcoma [ Hum Cell, 2020, 10.1007/s13577-020-00420-z] PubMed: 32870449

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NIET VOOR HUMANE, VETERINAIRE DIAGNOSTISCHE OF THERAPEUTISCHE DOELEINDEN.