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XL147 analogue

Catalog No.S1118

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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XL147 analogue Chemical Structure
Molecular Weight: 448.52

Validation & Quality Control

Cited by 5 publications：

Autophagy,2012, 8(6):903-14

Full text(PDF)

Cancer Res,2014, 74(18):5184-94

PubMed: 25100563

Oncogene,2015, 10.1038/onc.2015.143

PubMed: 25961924

PLoS One,2014, 9(8):e105280

Full text(PDF)

Head Neck,2014, 10.1002/hed.23822

Full text(PDF)

2 customer reviews : in vivo invitation

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

Quality Control & MSDS

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XL147 analogue is available in the following compound libraries:

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Product Information

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Research Area
Research Area
Inhibition Profile
Inhibition Profile
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.
2010 ASCO Annual Meeting

Cat.No.	Product Name	Solubility (25°C)
S1009	BEZ235 (NVP-BEZ235, Dactolisib)	<1 mg/mL	0.01 mg/mL	<1 mg/mL
S1065	Pictilisib (GDC-0941)	<1 mg/mL	44 mg/mL	<1 mg/mL
S1105	LY294002	<1 mg/mL	36 mg/mL	21 mg/mL
S2226	CAL-101 (Idelalisib, GS-1101)	<1 mg/mL	83 mg/mL	23 mg/mL
S2247	BKM120 (NVP-BKM120, Buparlisib)	<1 mg/mL	82 mg/mL	2 mg/mL
S1038	PI-103	<1 mg/mL	24 mg/mL	<1 mg/mL
S2638	NU7441 (KU-57788)	<1 mg/mL	3 mg/mL	<1 mg/mL
S1169	TGX-221	<1 mg/mL	12 mg/mL	<1 mg/mL
S1268	IC-87114	<1 mg/mL	0.66 mg/mL	<1 mg/mL
S2758	Wortmannin	<1 mg/mL	85 mg/mL	<1 mg/mL
S1118	XL147 analogue	<1 mg/mL	3 mg/mL	<1 mg/mL
S1072	ZSTK474	<1 mg/mL	21 mg/mL	<1 mg/mL
S2814	Alpelisib (BYL719)	<1 mg/mL	88 mg/mL	2 mg/mL
S1410	AS-605240	<1 mg/mL	0.4 mg/mL	<1 mg/mL
S1205	PIK-75	<1 mg/mL	3 mg/mL	<1 mg/mL
S2767	3-Methyladenine (3-MA)	20 mg/mL	3 mg/mL	4 mg/mL
S2636	A66	<1 mg/mL	79 mg/mL	1 mg/mL
S1523	Voxtalisib (SAR245409, XL765) Analogue	<1 mg/mL	12 mg/mL	<1 mg/mL
S1489	PIK-93	<1 mg/mL	78 mg/mL	<1 mg/mL
S2658	Omipalisib (GSK2126458, GSK458)	<1 mg/mL	100 mg/mL	<1 mg/mL
S1187	PIK-90	<1 mg/mL	0.28 mg/mL	<1 mg/mL
S2743	PF-04691502	<1 mg/mL	14 mg/mL	<1 mg/mL
S1462	AZD6482	<1 mg/mL	82 mg/mL	10 mg/mL
S2696	Apitolisib (GDC-0980, RG7422)	<1 mg/mL	20 mg/mL	<1 mg/mL
S1360	GSK1059615	<1 mg/mL	2 mg/mL	<1 mg/mL
S7028	Duvelisib (IPI-145, INK1197)	<1 mg/mL	83 mg/mL	<1 mg/mL
S2628	Gedatolisib (PF-05212384, PKI-587)	<1 mg/mL	2 mg/mL	<1 mg/mL
S1352	TG100-115	<1 mg/mL	9 mg/mL	<1 mg/mL
S2671	AS-252424	<1 mg/mL	61 mg/mL	<1 mg/mL
S2749	BGT226 (NVP-BGT226)	<1 mg/mL	30 mg/mL	<1 mg/mL
S2759	CUDC-907	<1 mg/mL	102 mg/mL	<1 mg/mL
S2227	PIK-294	<1 mg/mL	98 mg/mL	<1 mg/mL
S2681	AS-604850	<1 mg/mL	57 mg/mL	5 mg/mL
S8002	GSK2636771	<1 mg/mL	28 mg/mL	<1 mg/mL
S2802	BAY 80-6946 (Copanlisib)	0.002 mg/mL	0.002 mg/mL	0.01 mg/mL
S1219	YM201636	<1 mg/mL	35 mg/mL	<1 mg/mL
S2699	CH5132799	<1 mg/mL	12 mg/mL	<1 mg/mL
S2682	CAY10505	<1 mg/mL	58 mg/mL	<1 mg/mL
S2207	PIK-293	<1 mg/mL	80 mg/mL	<1 mg/mL
S2739	PKI-402	<1 mg/mL	0.4 mg/mL	<1 mg/mL
S2870	TG100713	<1 mg/mL	2 mg/mL	<1 mg/mL
S7016	VS-5584 (SB2343)	<1 mg/mL	71 mg/mL	3 mg/mL
S7103	GDC-0032	<1 mg/mL	70 mg/mL	<1 mg/mL
S7018	CZC24832	<1 mg/mL	5 mg/mL	<1 mg/mL
S7798	GNE-317	<1 mg/mL	47 mg/mL	<1 mg/mL
S7356	HS-173	<1 mg/mL	84 mg/mL	<1 mg/mL
S7623	PI-3065	<1 mg/mL	50 mg/mL	<1 mg/mL
S7645	Pilaralisib (XL147)	<1 mg/mL	100 mg/mL	<1 mg/mL
S7675	PF-4989216	<1 mg/mL	76 mg/mL	7 mg/mL
S7694	AZD8186	<1 mg/mL	91 mg/mL	35 mg/mL
S7813	AMG319	<1 mg/mL	77 mg/mL	77 mg/mL
S7646	Voxtalisib (XL765, SAR245409)	<1 mg/mL	54 mg/mL	<1 mg/mL

Product Description

Biological Activity Protocol Clinical Trial Information Chemical Information FAQ Tech Support

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)	View More
IC50	23 nM	36 nM	39 nM	383 nM	View More
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 p27^KIPI 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 pAKT^S473/T308 and pS6^S240/244. Surprisingly, XL147 also triggers up-regulation of total HER3 and/or pHER3^Y1289 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]
Features

Protocol(Only for Reference)

Cell Assay:
^[2]

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.

Animal Study:
^[2]

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

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m²)	0.007	0.025	0.15	0.05	0.02	0.5
K_m factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B K_m
	Animal A K_m

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 K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×	mouse K_m(3)	= 11.2 mg/kg
	rat K_m(6)

References

[1] 2010 ASCO Annual Meeting

[2] Chakrabarty A, et al. Proc Natl Acad Sci U S A, 2011, 1-6.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

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

view more

Chemical Information

Download XL147 analogue SDF

Molecular Weight (MW)	448.52
Formula	C₂₁H₁₆N₆O₂S₂
CAS No.	956958-53-5

Storage	3 years -20℃powder
Storage	6 months-80℃in solvent
Synonyms	SAR245408

Solubility (25°C) *	In vitro	DMSO	3 mg/mL (6.68 mM)
		Water	<1 mg/mL (<1 mM)
		Ethanol	<1 mg/mL (<1 mM)
	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 Name	N-(3-(benzo[c][1,2,5]thiadiazol-5-ylamino)quinoxalin-2-yl)-4-methylbenzenesulfonamide

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Tech Support

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XL147 analogue