Pilaralisib | XL-147 | CAS#956958-53-5 | 934526-89-3 | PI3K inhibior

MedKoo Cat#: 203181 | Name: Pilaralisib

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Pilaralisib, also known as XL147, is a Class 1 PI3K kinase family inhibitor with potential antineoplastic activity. XL147 reversibly binds to class 1 PI3Ks in an ATP-competitive manner, inhibiting the production of the secondary messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3) and activation of the PI3K signaling pathway; this may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis.

Chemical Structure

Pilaralisib

CAS#934526-89-3

Theoretical Analysis

MedKoo Cat#: 203181

Name: Pilaralisib

CAS#: 934526-89-3

Chemical Formula: C25H25ClN6O4S

Exact Mass: 540.1347

Molecular Weight: 541.02

Elemental Analysis: C, 55.50; H, 4.66; Cl, 6.55; N, 15.53; O, 11.83; S, 5.93

Price and Availability

Size	Price	Availability
50mg	USD 250.00	2 Weeks
100mg	USD 450.00	2 Weeks
200mg	USD 750.00	2 Weeks
500mg	USD 1,450.00	2 Weeks
1g	USD 2,650.00	2 Weeks
2g	USD 4,250.00	2 Weeks

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Related CAS #

934526-89-3 956958-53-5.

Synonym

XL147; XL 147; XL-147; SAR245408; SAR-245408; SAR 245408; Pilaralisib.

IUPAC/Chemical Name

2-amino-N-(3-(N-(3-((2-chloro-5-methoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methylpropanamide.

InChi Key

QINPEPAQOBZPOF-UHFFFAOYSA-N

InChi Code

InChI=1S/C25H25ClN6O4S/c1-25(2,27)24(33)28-15-7-6-8-17(13-15)37(34,35)32-23-22(29-19-9-4-5-10-20(19)30-23)31-21-14-16(36-3)11-12-18(21)26/h4-14H,27H2,1-3H3,(H,28,33)(H,29,31)(H,30,32)

SMILES Code

CC(C)(N)C(NC1=CC=CC(S(=O)(NC2=NC3=CC=CC=C3N=C2NC4=CC(OC)=CC=C4Cl)=O)=C1)=O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Exelixis is developing XL147 in collaboration with sanofi-aventis. Based on clinical data available to date, XL147 appears to be well tolerated and has shown clinical activity in a range of cancer types. As a result, Exelixis and sanofi-aventis are pursuing a broad clinical development program for XL147, evaluating the compound as a single agent and in multiple combination regimens in a variety of cancer indications. Ongoing clinical trials include a phase 2 trial in endometrial cancer, phase 1b/2 trials in combination with carboplatin and paclitaxel in patients with endometrial, ovarian or non-small cell lung cancer (NSCLC), in combination with erlotinib in patients with NSCLC, and in combination with trastuzumab or trastuzumab and paclitaxel in patients with HER2-positive breast cancer, and a phase 1 trial in patients with solid tumors or lymphoma. (source: http://www.exelixis.com/pipeline/xl147).

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Pilaralisib (XL147; SAR245408) is a potent and highly selective class I PI3Ks inhibitor with IC50s of 39 nM, 383 nM, 23 nM and 36 nM for PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ.

In vitro activity:

XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. Reference: Mol Cancer Ther. 2015 Apr;14(4):931-40. https://pubmed.ncbi.nlm.nih.gov/25637314/

In vivo activity:

SAR245408 was well tolerated in vivo, and all 44 tested xenograft models were evaluable for efficacy. SAR245408 induced significant differences in EFS distribution compared to control in 29 of 37 (79%) of solid tumor xenografts and in two of seven (29%) ALL xenografts. SAR245408 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C > 2) in 4 of 37 (11%) solid tumor xenografts. Reference: Pediatr Blood Cancer. 2013 May;60(5):791-8. https://pubmed.ncbi.nlm.nih.gov/23002019/

	Solvent	mg/mL	mM
Solubility
	DMF	20.0	36.97
	DMSO	60.0	110.90
	DMSO:PBS (pH 7.2) (1:30)	0.0	0.06

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 541.02 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Foster P, Yamaguchi K, Hsu PP, Qian F, Du X, Wu J, Won KA, Yu P, Jaeger CT, Zhang W, Marlowe CK, Keast P, Abulafia W, Chen J, Young J, Plonowski A, Yakes FM, Chu F, Engell K, Bentzien F, Lam ST, Dale S, Yturralde O, Matthews DJ, Lamb P, Laird AD. The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models. Mol Cancer Ther. 2015 Apr;14(4):931-40. doi: 10.1158/1535-7163.MCT-14-0833. Epub 2015 Jan 30. PMID: 25637314. 2. Reynolds CP, Kang MH, Carol H, Lock R, Gorlick R, Kolb EA, Kurmasheva RT, Keir ST, Maris JM, Billups CA, Houghton PJ, Smith MA. Initial testing (stage 1) of the phosphatidylinositol 3' kinase inhibitor, SAR245408 (XL147) by the pediatric preclinical testing program. Pediatr Blood Cancer. 2013 May;60(5):791-8. doi: 10.1002/pbc.24301. Epub 2012 Sep 21. PMID: 23002019; PMCID: PMC4684943.

In vitro protocol:

In vivo protocol:

1: Strub MD, Ramachandran S, Boudko DY, Meleshkevitch EA, Pezzulo AA, Subramanian A, Liberzon A, Bridges RJ, McCray PB Jr. Translating in vitro CFTR rescue into small molecule correctors for cystic fibrosis using the Library of Integrated Network-based Cellular Signatures drug discovery platform. CPT Pharmacometrics Syst Pharmacol. 2022 Feb;11(2):240-251. doi: 10.1002/psp4.12751. Epub 2021 Dec 23. PMID: 34877817; PMCID: PMC8846631. 2: Cooper L, Schafer A, Li Y, Cheng H, Medegan Fagla B, Shen Z, Nowar R, Dye K, Anantpadma M, Davey RA, Thatcher GRJ, Rong L, Xiong R. Screening and Reverse- Engineering of Estrogen Receptor Ligands as Potent Pan-Filovirus Inhibitors. J Med Chem. 2020 Oct 8;63(19):11085-11099. doi: 10.1021/acs.jmedchem.0c01001. Epub 2020 Sep 22. PMID: 32886512; PMCID: PMC7904233. 3: Xiao Y, Yu Y, Jiang P, Li Y, Wang C, Zhang R. The PI3K/mTOR dual inhibitor GSK458 potently impedes ovarian cancer tumorigenesis and metastasis. Cell Oncol (Dordr). 2020 Aug;43(4):669-680. doi: 10.1007/s13402-020-00514-8. Epub 2020 May 8. PMID: 32382996. 4: Jiang Z, Gong T, Wei H. CDKL5 promotes proliferation, migration, and chemotherapeutic drug resistance of glioma cells via activation of the PI3K/AKT signaling pathway. FEBS Open Bio. 2020 Feb;10(2):268-277. doi: 10.1002/2211-5463.12780. Epub 2020 Jan 21. PMID: 31858726; PMCID: PMC6996333. 5: Sharick JT, Jeffery JJ, Karim MR, Walsh CM, Esbona K, Cook RS, Skala MC. Cellular Metabolic Heterogeneity In Vivo Is Recapitulated in Tumor Organoids. Neoplasia. 2019 Jun;21(6):615-626. doi: 10.1016/j.neo.2019.04.004. Epub 2019 May 9. PMID: 31078067; PMCID: PMC6514366. 6: Zhou Y, Zhang Q, Du M, Xiong D, Wang Y, Mohammed A, Lubet RA, Wang L, You M. Exosomal miRNAs as Novel Pharmacodynamic Biomarkers for Cancer Chemopreventive Agent Early Stage Treatments in Chemically Induced Mouse Model of Lung Squamous Cell Carcinoma. Cancers (Basel). 2019 Apr 4;11(4):477. doi: 10.3390/cancers11040477. PMID: 30987362; PMCID: PMC6520832. 7: Shah N, Mohammad AS, Saralkar P, Sprowls SA, Vickers SD, John D, Tallman RM, Lucke-Wold BP, Jarrell KE, Pinti M, Nolan RL, Lockman PR. Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases. Pharmacol Res. 2018 Jun;132:47-68. doi: 10.1016/j.phrs.2018.03.021. Epub 2018 Mar 28. PMID: 29604436; PMCID: PMC5997530. 8: Edelman G, Rodon J, Lager J, Castell C, Jiang J, Van Allen EM, Wagle N, Lindeman NI, Sholl LM, Shapiro GI. Phase I Trial of a Tablet Formulation of Pilaralisib, a Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors. Oncologist. 2018 Apr;23(4):401-e38. doi: 10.1634/theoncologist.2017-0691. Epub 2018 Mar 28. PMID: 29593099; PMCID: PMC5896717. 9: Tang L, Long Z, Zhao N, Feng G, Guo X, Yu M. NES1/KLK10 promotes trastuzumab resistance via activation of PI3K/AKT signaling pathway in gastric cancer. J Cell Biochem. 2018 Aug;119(8):6398-6407. doi: 10.1002/jcb.26562. Epub 2018 Apr 17. PMID: 29231994. 10: Bosbach B, Rossi F, Yozgat Y, Loo J, Zhang JQ, Berrozpe G, Warpinski K, Ehlers I, Veach D, Kwok A, Manova K, Antonescu CR, DeMatteo RP, Besmer P. Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor. Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):E8448-E8457. doi: 10.1073/pnas.1711449114. Epub 2017 Sep 18. PMID: 28923937; PMCID: PMC5635919. 11: Cannon TM, Shah AT, Skala MC. Autofluorescence imaging captures heterogeneous drug response differences between 2D and 3D breast cancer cultures. Biomed Opt Express. 2017 Feb 28;8(3):1911-1925. doi: 10.1364/BOE.8.001911. PMID: 28663873; PMCID: PMC5480588. 12: Wheler J, Mutch D, Lager J, Castell C, Liu L, Jiang J, Traynor AM. Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147) in Combination with Paclitaxel and Carboplatin in Patients with Solid Tumors. Oncologist. 2017 Apr;22(4):377-e37. doi: 10.1634/theoncologist.2016-0257. Epub 2017 Mar 8. PMID: 28275119; PMCID: PMC5388374. 13: Abramson VG, Supko JG, Ballinger T, Cleary JM, Hilton JF, Tolaney SM, Chau NG, Cho DC, Pearlberg J, Lager J, Shapiro GI, Arteaga CL. Phase Ib Study of Safety and Pharmacokinetics of the PI3K Inhibitor SAR245408 with the HER3-Neutralizing Human Antibody SAR256212 in Patients with Solid Tumors. Clin Cancer Res. 2017 Jul 15;23(14):3520-3528. doi: 10.1158/1078-0432.CCR-16-1764. Epub 2016 Dec 28. PMID: 28031425. 14: Xiong D, Pan J, Zhang Q, Szabo E, Miller MS, Lubet RA, You M, Wang Y. Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents. Oncotarget. 2017 Mar 21;8(12):18885-18900. doi: 10.18632/oncotarget.13806. PMID: 27935865; PMCID: PMC5386655. 15: Zhang WL, Ma WJ, Chen S, Wu XZ, Zhang HR, Zhang JH. [Molecular mechanisms of resistance to phosphatidyl inositol 3-kinase inhibitors in triple-negative breast cancer cells]. Zhonghua Zhong Liu Za Zhi. 2016 Aug;38(8):578-88. Chinese. doi: 10.3760/cma.j.issn.0253-3766.2016.08.004. PMID: 27531477. 16: Bechter OE, Dumez H, Costermans J, Punie K, Hsu K, Dedieu JF, Ghuysen AF, Francesconi E, Sharma J, Liu L, Schöffski P. Phase I safety and pharmacokinetic dose-escalation study of pilaralisib polymorph E, a phosphoinositide 3-kinase inhibitor in tablet formulation, in patients with solid tumors or lymphoma. Cancer Chemother Pharmacol. 2016 Jul;78(1):83-90. doi: 10.1007/s00280-016-3056-0. Epub 2016 May 11. PMID: 27169794. 17: Hayashida Y, Ikeda Y, Sawada K, Kawai K, Kato T, Kakehi Y, Araki N. Invention of a novel photodynamic therapy for tumors using a photosensitizing PI3K inhibitor. Int J Cancer. 2016 Aug 1;139(3):700-11. doi: 10.1002/ijc.30097. Epub 2016 Apr 6. PMID: 26989815. 18: Setti A, Kumar MJ, Babu KR, Rasagna A, Prasanna MG, Devi TA, Pawar SC. Potency and pharmacokinetics of broad spectrum and isoform-specific p110γ and δ inhibitors in cancers. J Recept Signal Transduct Res. 2016;36(1):26-36. doi: 10.3109/10799893.2014.1003658. Epub 2015 Oct 13. PMID: 26791581. 19: Blackwell K, Burris H, Gomez P, Lynn Henry N, Isakoff S, Campana F, Gao L, Jiang J, Macé S, Tolaney SM. Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2-negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor. Breast Cancer Res Treat. 2015 Nov;154(2):287-97. doi: 10.1007/s10549-015-3615-9. Epub 2015 Oct 24. PMID: 26497877. 20: Gravina GL, Mancini A, Scarsella L, Colapietro A, Jitariuc A, Vitale F, Marampon F, Ricevuto E, Festuccia C. Dual PI3K/mTOR inhibitor, XL765 (SAR245409), shows superior effects to sole PI3K [XL147 (SAR245408)] or mTOR [rapamycin] inhibition in prostate cancer cell models. Tumour Biol. 2016 Jan;37(1):341-51. doi: 10.1007/s13277-015-3725-3. Epub 2015 Jul 29. PMID: 26219891.