PF-04691502 | CAS#1013101-36-4 | PI3K/mTOR inhibitor

MedKoo Cat#: 202226 | Name: PF-04691502

Description:

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

PF-04691502 is a PI3K/mTOR kinase inhibitor , is also an agent targeting the phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. PI3K/mTOR kinase inhibitor PF-04691502 inhibits both PI3K and mTOR kinases, which may result in apoptosis and growth inhibition of cancer cells overexpressing PI3K/mTOR.

Chemical Structure

PF-04691502

CAS#1013101-36-4

Theoretical Analysis

MedKoo Cat#: 202226

Name: PF-04691502

CAS#: 1013101-36-4

Chemical Formula: C22H27N5O4

Exact Mass: 425.2063

Molecular Weight: 425.48

Elemental Analysis: C, 62.10; H, 6.40; N, 16.46; O, 15.04

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,850.00	Ready to ship
1g	USD 3,650.00	Ready to ship

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Synonym

PF04691502; PF 04691502; PF-04691502; PF4691502; PF 4691502; PF-4691502.

IUPAC/Chemical Name

2-amino-8-((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

InChi Key

XDLYKKIQACFMJG-WKILWMFISA-N

InChi Code

InChI=1S/C22H27N5O4/c1-13-17-11-18(14-3-8-19(30-2)24-12-14)21(29)27(20(17)26-22(23)25-13)15-4-6-16(7-5-15)31-10-9-28/h3,8,11-12,15-16,28H,4-7,9-10H2,1-2H3,(H2,23,25,26)/t15-,16-

SMILES Code

O=C1C(C2=CC=C(OC)N=C2)=CC3=C(C)N=C(N)N=C3N1[C@H]4CC[C@H](OCCO)CC4

Appearance

Solid powder

Purity

>97 % (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

Shelf Life

>5 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

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#C8R05B29

QC Data

View QC data: current batch, Lot#C8R05B29

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

PF-04691502 is an inhibitor of PI3K and mTOR. PF-04691502 binds to human PI3Kα, β, δ, γ and mTOR with Kis of 1.8, 2.1, 1.6, 1.9 and 16 nM, respectively.

In vitro activity:

This study treated QGP-1 and BON cells with PF-04691502 (500 nM) to test the duration of PI3K pathway inhibition (Figure 2C). The expression of pAkt was inhibited in both QGP-1 and BON cells at 24, 48 and 72 h. Similarly, expression of pS6 (Ser235/236), which is a key regulator of 40 S ribosome subunit biogenesis, was inhibited in both cell lines. Finally, this study assessed the expression of p4EBP-1 (Thr37/46), which plays a critical role in translational mRNA complex assembly and found that PF-04691502 (500 nM) inhibited expression of this protein at all time points; p4EBP-1 expression was markedly attenuated at 24 and 48 h and completely inhibited at 72 h. A single treatment with PF-04691502 not only demonstrated sustained inhibition for the 24 h period in QGP-1 and BON cells (Figure 2B), but also attenuated pAkt, pS6 and p4EBP-1 at 24 h in NT-3 cells (data not shown). Moreover, these results demonstrate that PF-04691502 can effectively inhibit PI3K/mTOR pathway components in both QGP-1 and BON cells for at least 72 h. Reference: Cells. 2021 May 20;10(5):1261. https://pubmed.ncbi.nlm.nih.gov/34065268/

In vivo activity:

Finally, this study tested the antitumor activity of PF-502 (PF-04691502) in vivo using a xenograft mouse model. HH cells were transplanted subcutaneously into the flank of nude mice. When the tumors reached a 300 mm3 mean volume, the mice were randomized into two groups (eight mice per group): the group treated with PF-502 and the vehicle control group. Immunohistochemistry analysis of tumor specimens harvested 1 hour after PF-502 injection, confirmed the inhibition of TORC1 and TORC2 signaling compared with the control group, as measured by P-S6RP(Ser235/236) and P-AKT(Ser473) (Supplementary Figure S5). PF-502 exhibited robust antitumor activity from day 4 of treatment (Figure 5a), reaching significance on day 13 (P < 0.005). At the end of the treatment, the tumor size in the PF-502-treated group was 43% of the control group (400 ± 57 mm3 vs 936 ± 158 mm3, P < 0.001). Accordingly, the mean tumor weight in the PF-502 group was 36% of the controls (0.2 ± 0.05 g vs 0.56 ± 0.05 g, P < 0.001) (Figure 5b). Furthermore, the Kaplan-Meier curve revealed PF-502 treatment prolongs survival: The control group showed a median time-to-event of 19 days while all, but one, PF-502-treated mice, did not reach the predefined endpoint by the end of the experiment (day 28, P < 0.005, Figure 5c). Reference: J Invest Dermatol. 2020 May;140(5):1045-1053.e6. https://pubmed.ncbi.nlm.nih.gov/31682844/

	Solvent	mg/mL	mM
Solubility
	DMSO	14.0	32.90

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 425.48 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. Chow Z, Johnson J, Chauhan A, Izumi T, Cavnar M, Weiss H, Townsend CM Jr, Anthony L, Wasilchenko C, Melton ML, Schrader J, Evers BM, Rychahou P. PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors. Cells. 2021 May 20;10(5):1261. doi: 10.3390/cells10051261. PMID: 34065268. 2. Yuan J, Mehta PP, Yin MJ, Sun S, Zou A, Chen J, Rafidi K, Feng Z, Nickel J, Engebretsen J, Hallin J, Blasina A, Zhang E, Nguyen L, Sun M, Vogt PK, McHarg A, Cheng H, Christensen JG, Kan JL, Bagrodia S. PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity. Mol Cancer Ther. 2011 Nov;10(11):2189-99. doi: 10.1158/1535-7163.MCT-11-0185. Epub 2011 Jul 12. PMID: 21750219. 3. Bresin A, Cristofoletti C, Caprini E, Cantonetti M, Monopoli A, Russo G, Narducci MG. Preclinical Evidence for Targeting PI3K/mTOR Signaling with Dual-Inhibitors as a Therapeutic Strategy against Cutaneous T-Cell Lymphoma. J Invest Dermatol. 2020 May;140(5):1045-1053.e6. doi: 10.1016/j.jid.2019.08.454. Epub 2019 Nov 1. PMID: 31682844. 4. Blunt MD, Carter MJ, Larrayoz M, Smith LD, Aguilar-Hernandez M, Cox KL, Tipton T, Reynolds M, Murphy S, Lemm E, Dias S, Duncombe A, Strefford JC, Johnson PW, Forconi F, Stevenson FK, Packham G, Cragg MS, Steele AJ. The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the Eµ-TCL1 mouse model. Blood. 2015 Jun 25;125(26):4032-41. doi: 10.1182/blood-2014-11-610329. Epub 2015 May 8. PMID: 25957390.

In vitro protocol:

In vivo protocol:

1. Bresin A, Cristofoletti C, Caprini E, Cantonetti M, Monopoli A, Russo G, Narducci MG. Preclinical Evidence for Targeting PI3K/mTOR Signaling with Dual-Inhibitors as a Therapeutic Strategy against Cutaneous T-Cell Lymphoma. J Invest Dermatol. 2020 May;140(5):1045-1053.e6. doi: 10.1016/j.jid.2019.08.454. Epub 2019 Nov 1. PMID: 31682844. 2. Blunt MD, Carter MJ, Larrayoz M, Smith LD, Aguilar-Hernandez M, Cox KL, Tipton T, Reynolds M, Murphy S, Lemm E, Dias S, Duncombe A, Strefford JC, Johnson PW, Forconi F, Stevenson FK, Packham G, Cragg MS, Steele AJ. The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the Eµ-TCL1 mouse model. Blood. 2015 Jun 25;125(26):4032-41. doi: 10.1182/blood-2014-11-610329. Epub 2015 May 8. PMID: 25957390.

1: Fan Z, Tong Y, Yang Z, Wang S, Huang T, Yang D, Ni Q, Zhang M, Li D, Yang M, Fan X. Inhibitor PF-04691502 works as a senolytic to regulate cellular senescence. Exp Gerontol. 2024 Feb;186:112359. doi: 10.1016/j.exger.2024.112359. Epub 2024 Jan 7. PMID: 38184267. 2: Fujinaga A, Hirashita T, Hirashita Y, Sakai K, Kawamura M, Masuda T, Endo Y, Ohta M, Murakami K, Inomata M. Glucose metabolic upregulation via phosphorylation of S6 ribosomal protein affects tumor progression in distal cholangiocarcinoma. BMC Gastroenterol. 2023 May 16;23(1):157. doi: 10.1186/s12876-023-02815-2. PMID: 37193984; PMCID: PMC10190040. 3: Li Z, Zhou H, Xia Z, Xia T, Du G, Franziska SD, Li X, Zhai X, Jin B. HMGA1 augments palbociclib efficacy via PI3K/mTOR signaling in intrahepatic cholangiocarcinoma. Biomark Res. 2023 Mar 29;11(1):33. doi: 10.1186/s40364-023-00473-w. Erratum in: Biomark Res. 2024 Feb 16;12(1):27. doi: 10.1186/s40364-024-00574-0. PMID: 36978140; PMCID: PMC10053751. 4: Yang Q, Ma X, Xiao Y, Zhang T, Yang L, Yang S, Liang M, Wang S, Wu Z, Xu Z, Sun Z. Engineering prodrug nanomicelles as pyroptosis inducer for codelivery of PI3K/mTOR and CDK inhibitors to enhance antitumor immunity. Acta Pharm Sin B. 2022 Jul;12(7):3139-3155. doi: 10.1016/j.apsb.2022.02.024. Epub 2022 Feb 26. PMID: 35865097; PMCID: PMC9293721. 5: Shang X, Na X, Wang L, Yang Z, Ren P. Evaluation of a Dual PI3K/mTOR Inhibitor PF-04691502 against Bladder Cancer Cells. Evid Based Complement Alternat Med. 2022 Jun 24;2022:8110796. doi: 10.1155/2022/8110796. PMID: 35783514; PMCID: PMC9249467. 6: Sohn EJ. PIK3R3, a regulatory subunit of PI3K, modulates ovarian cancer stem cells and ovarian cancer development and progression by integrative analysis. BMC Cancer. 2022 Jun 27;22(1):708. doi: 10.1186/s12885-022-09807-7. PMID: 35761259; PMCID: PMC9238166. 7: Darici S, Zavatti M, Braglia L, Accordi B, Serafin V, Horne GA, Manzoli L, Palumbo C, Huang X, Jørgensen HG, Marmiroli S. Synergistic cytotoxicity of dual PI3K/mTOR and FLT3 inhibition in FLT3-ITD AML cells. Adv Biol Regul. 2021 Dec;82:100830. doi: 10.1016/j.jbior.2021.100830. Epub 2021 Sep 17. PMID: 34555701. 8: Tierney C, Bazou D, Majumder MM, Anttila P, Silvennoinen R, Heckman CA, Dowling P, O'Gorman P. Next generation proteomics with drug sensitivity screening identifies sub-clones informing therapeutic and drug development strategies for multiple myeloma patients. Sci Rep. 2021 Jun 18;11(1):12866. doi: 10.1038/s41598-021-90149-y. PMID: 34145309; PMCID: PMC8213739. 9: Chow Z, Johnson J, Chauhan A, Izumi T, Cavnar M, Weiss H, Townsend CM Jr, Anthony L, Wasilchenko C, Melton ML, Schrader J, Evers BM, Rychahou P. PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors. Cells. 2021 May 20;10(5):1261. doi: 10.3390/cells10051261. PMID: 34065268; PMCID: PMC8160730. 10: Huang WK, Chen Y, Su H, Chen TY, Gao J, Liu Y, Yeh CN, Li S. ARHGAP25 Inhibits Pancreatic Adenocarcinoma Growth by Suppressing Glycolysis via AKT/mTOR Pathway. Int J Biol Sci. 2021 Apr 24;17(7):1808-1820. doi: 10.7150/ijbs.55919. PMID: 33994864; PMCID: PMC8120455. 11: Kanasugi J, Hanamura I, Ota A, Karnan S, Lam VQ, Mizuno S, Wahiduzzaman M, Rahman ML, Hyodo T, Konishi H, Tsuzuki S, Hosokawa Y, Takami A. Biallelic loss of FAM46C triggers tumor growth with concomitant activation of Akt signaling in multiple myeloma cells. Cancer Sci. 2020 May;111(5):1663-1675. doi: 10.1111/cas.14386. Epub 2020 Apr 9. PMID: 32176823; PMCID: PMC7226186. 12: Langdon SP, Kay C, Um IH, Dodds M, Muir M, Sellar G, Kan J, Gourley C, Harrison DJ. Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models. Sci Rep. 2019 Dec 10;9(1):18742. doi: 10.1038/s41598-019-55096-9. PMID: 31822716; PMCID: PMC6904563. 13: Wang H, Cao Y, Shu L, Zhu Y, Peng Q, Ran L, Wu J, Luo Y, Zuo G, Luo J, Zhou L, Shi Q, Weng Y, Huang A, He TC, Fan J. Long non-coding RNA (lncRNA) H19 induces hepatic steatosis through activating MLXIPL and mTORC1 networks in hepatocytes. J Cell Mol Med. 2020 Jan;24(2):1399-1412. doi: 10.1111/jcmm.14818. Epub 2019 Dec 6. Erratum in: J Cell Mol Med. 2023 Apr;27(7):1021-1022. doi: 10.1111/jcmm.17719. PMID: 31809000; PMCID: PMC6991647. 14: Bresin A, Cristofoletti C, Caprini E, Cantonetti M, Monopoli A, Russo G, Narducci MG. Preclinical Evidence for Targeting PI3K/mTOR Signaling with Dual- Inhibitors as a Therapeutic Strategy against Cutaneous T-Cell Lymphoma. J Invest Dermatol. 2020 May;140(5):1045-1053.e6. doi: 10.1016/j.jid.2019.08.454. Epub 2019 Nov 1. PMID: 31682844. 15: Zainal NS, Lee BKB, Wong ZW, Chin IS, Yee PS, Gan CP, Mun KS, Rahman ZAA, Gutkind JS, Patel V, Cheong SC. Effects of palbociclib on oral squamous cell carcinoma and the role of PIK3CA in conferring resistance. Cancer Biol Med. 2019 May;16(2):264-275. doi: 10.20892/j.issn.2095-3941.2018.0257. PMID: 31516747; PMCID: PMC6713638. 16: Chang X, Suo L, Xu N, Zhao Y. Orexin-A Stimulates Insulin Secretion Through the Activation of the OX1 Receptor and Mammalian Target of Rapamycin in Rat Insulinoma Cells. Pancreas. 2019 Apr;48(4):568-573. doi: 10.1097/MPA.0000000000001280. PMID: 30946236. 17: Islam S, Vick E, Huber B, Morales C, Spier C, Cooke L, Weterings E, Mahadevan D. Co-targeting aurora kinase with PD-L1 and PI3K abrogates immune checkpoint mediated proliferation in peripheral T-cell lymphoma: a novel therapeutic strategy. Oncotarget. 2017 Nov 1;8(59):100326-100338. doi: 10.18632/oncotarget.22222. PMID: 29245981; PMCID: PMC5725023. 18: Brana I, Pham NA, Kim L, Sakashita S, Li M, Ng C, Wang Y, Loparco P, Sierra R, Wang L, Clarke BA, Neel BG, Siu LL, Tsao MS. Novel combinations of PI3K-mTOR inhibitors with dacomitinib or chemotherapy in PTEN-deficient patient-derived tumor xenografts. Oncotarget. 2017 Jul 8;8(49):84659-84670. doi: 10.18632/oncotarget.19109. PMID: 29156674; PMCID: PMC5689564. 19: Wainberg ZA, Alsina M, Soares HP, Braña I, Britten CD, Del Conte G, Ezeh P, Houk B, Kern KA, Leong S, Pathan N, Pierce KJ, Siu LL, Vermette J, Tabernero J. A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer. Target Oncol. 2017 Dec;12(6):775-785. doi: 10.1007/s11523-017-0530-5. PMID: 29067643; PMCID: PMC5700209. 20: Qi Y, Hu Y, Yang H, Zhuang R, Hou Y, Tong H, Feng Y, Huang Y, Jiang Q, Ji Q, Gu Q, Zhang Z, Tang X, Lu W, Zhou Y. Establishing a patient-derived xenograft model of human myxoid and round-cell liposarcoma. Oncotarget. 2017 Apr 21;8(33):54320-54330. doi: 10.18632/oncotarget.17352. PMID: 28903344; PMCID: PMC5589583.