Gedatolisib
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MedKoo CAT#: 202255

CAS#: 1197160-78-3

Description: Gedatolisib, also known as PKI-587 and PF-05212384, is an agent targeting the phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. Upon intravenous administration, PI3K/mTOR kinase inhibitor PKI-587 inhibits both PI3K and mTOR kinases, which may result in apoptosis and growth inhibition of cancer cells overexpressing PI3K/mTOR. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy; mTOR, a serine/threonine kinase downstream of PI3K, may also be activated independent of PI3K.

Chemical Structure

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Gedatolisib
CAS# 1197160-78-3
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 202255
Name: Gedatolisib
CAS#: 1197160-78-3
Chemical Formula: C32H41N9O4
Exact Mass: 615.33
Molecular Weight: 615.720
Elemental Analysis: C, 62.42; H, 6.71; N, 20.47; O, 10.39

Price and Availability

Size Price Availability Quantity
5mg USD 90 Ready to ship
10mg USD 150 Ready to ship
25mg USD 250 Ready to ship
50mg USD 550 Ready to ship
100mg USD 950 Ready to ship
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Synonym: PKI587; PKI-587; PKI 587; PF05212384; PF-05212384; PF 05212384; PF5212384; PF-5212384; PF 5212384; Gedatolisib.

IUPAC/Chemical Name: 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea

InChi Key: DWZAEMINVBZMHQ-UHFFFAOYSA-N

InChi Code: InChI=1S/C32H41N9O4/c1-38(2)27-11-13-39(14-12-27)29(42)24-5-9-26(10-6-24)34-32(43)33-25-7-3-23(4-8-25)28-35-30(40-15-19-44-20-16-40)37-31(36-28)41-17-21-45-22-18-41/h3-10,27H,11-22H2,1-2H3,(H2,33,34,43)

SMILES Code: O=C(NC1=CC=C(C2=NC(N3CCOCC3)=NC(N4CCOCC4)=N2)C=C1)NC5=CC=C(C(N6CCC(N(C)C)CC6)=O)C=C5

Appearance: white 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: PKI-587 is a PI3K/mTOR inhibitor, currently being developed by Pfizer. The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. PKI-587  has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously.        

Biological target: Gedatolisib (PKI-587) is a dual inhibitor of PI3Kα, PI3Kγ, and mTOR with IC50s of 0.4 nM, 5.4 nM and 1.6 nM, respectively.
In vitro activity: In this study, two different gene expression datasets of relapsed patients also displayed a predominant enrichment of the PI3K/mTOR pathway. Using a panel of 88 different inhibitors which target several different components of this pathway, PKI-587 was found to be the most selective drug that induces apoptosis of T-ALL cell lines that are dependent on the activity of the PI3K/mTOR pathway. An important observation was made, that the inhibitor PKI-587 was effective even in the presence of micro-environmental factors. The use of conditioned medium from the bone marrow HS5 cells had very little or no effect on PKI-587-induced inhibition of cell growth. This is interesting since it has been suggested that the bone marrow microenvironment, presumably through cytokine production, helps to protect leukemic cells from drug-induced death and thereby contributes to therapy resistance. These findings provide a basis for the use of the dual specificity inhibitor PKI-587 as a promising drug for the treatment of T-ALL. These biological assays also suggest a strong ability of PKI-578 to block cell proliferation, colony formation and to induce apoptosis of T-ALL cell lines. Reference: Cancer Lett. 2017 Apr 28;392:9-16. https://pubmed.ncbi.nlm.nih.gov/28159681/
In vivo activity: Gedatolisib alone did not yield an obvious advantage in decreasing or preventing metastatic disease ompared to vehicle-treated mice. Nor did Gedatolisib augment dose-dense AC therapy in a manner consistent with alleviation of disease burden (Fig. 3b-f). Vehicle treated mice had a roughly equivalent number of DTCs in the left lobe of the lung compared to mice treated with AC, Gedatolisib, or Gedatolisib + AC (Fig. 3b-c). T4-2 cells delivered to athymic nude mice via intracardiac injection tend to form metastases in their skull, brain and adrenal glands. Regimens containing dose-dense AC yielded a significant and substantial decrease in average luciferase signal 410 in the skull and adrenal glands (Fig. 3d-e). Signal in all other tissues assessed, including brain, was unaffected (Fig. 3e-f). On its own, Gedatolisib did result in a significant decrease in luciferase signal 412 emitted from the kidneys and adrenal glands (Fig. 3e). However, priming with Gedatolisib did not enhance the efficacy of AC. In fact, the two mice with the highest brain luciferase signal in this study received the PI3K/mTOR inhibitor in addition to dose-dense AC regimen (Fig. 3e). These data demonstrate that Gedatolisib, alone or in combination with AC, does not reliably or significantly decrease metastatic burden or eradicate DTCs in a preclinical model of TNBC metastasis. On the contrary, dose-dense chemotherapy offers the best treatment option across metrics measured, and addition of Gedatolisib skews some of these metrics in the wrong direction. Reference: Mol Oncol. 2021 May 31. https://pubmed.ncbi.nlm.nih.gov/34058066/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 2.8 4.50
DMF 1.5 2.44
DMF:PBS (pH 7.2) (1:1) 0.5 0.81

Preparing Stock Solutions

The following data is based on the product molecular weight 615.72 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.

Recalculate based on batch purity %
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. Gazi M, Moharram SA, Marhäll A, Kazi JU. The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell acute lymphoblastic leukemia (T-ALL). Cancer Lett. 2017 Apr 28;392:9-16. doi: 10.1016/j.canlet.2017.01.035. Epub 2017 Feb 1. Erratum in: Cancer Lett. 2019 Oct 1;461:155. PMID: 28159681. 2. Freitag H, Christen F, Lewens F, Grass I, Briest F, Iwaszkiewicz S, Siegmund B, Grabowski P. Inhibition of mTOR's Catalytic Site by PKI-587 Is a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease. Neuroendocrinology. 2017;105(1):90-104. doi: 10.1159/000448843. Epub 2016 Aug 12. PMID: 27513674; PMCID: PMC5475233. 3. Shor RE, Dai J, Lee SY, Pisarsky L, Matei I, Lucotti S, Lyden D, Bissell MJ, Ghajar CM. The PI3K/mTOR inhibitor Gedatolisib eliminates dormant breast cancer cells in organotypic culture, but fails to prevent metastasis in preclinical settings. Mol Oncol. 2021 May 31. doi: 10.1002/1878-0261.13031. Epub ahead of print. PMID: 34058066. 4. Mallon R, Feldberg LR, Lucas J, Chaudhary I, Dehnhardt C, Santos ED, Chen Z, dos Santos O, Ayral-Kaloustian S, Venkatesan A, Hollander I. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res. 2011 May 15;17(10):3193-203. doi: 10.1158/1078-0432.CCR-10-1694. Epub 2011 Feb 15. PMID: 21325073.
In vitro protocol: 1. Gazi M, Moharram SA, Marhäll A, Kazi JU. The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell acute lymphoblastic leukemia (T-ALL). Cancer Lett. 2017 Apr 28;392:9-16. doi: 10.1016/j.canlet.2017.01.035. Epub 2017 Feb 1. Erratum in: Cancer Lett. 2019 Oct 1;461:155. PMID: 28159681. 2. Freitag H, Christen F, Lewens F, Grass I, Briest F, Iwaszkiewicz S, Siegmund B, Grabowski P. Inhibition of mTOR's Catalytic Site by PKI-587 Is a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease. Neuroendocrinology. 2017;105(1):90-104. doi: 10.1159/000448843. Epub 2016 Aug 12. PMID: 27513674; PMCID: PMC5475233.
In vivo protocol: 1. Shor RE, Dai J, Lee SY, Pisarsky L, Matei I, Lucotti S, Lyden D, Bissell MJ, Ghajar CM. The PI3K/mTOR inhibitor Gedatolisib eliminates dormant breast cancer cells in organotypic culture, but fails to prevent metastasis in preclinical settings. Mol Oncol. 2021 May 31. doi: 10.1002/1878-0261.13031. Epub ahead of print. PMID: 34058066. 2. Mallon R, Feldberg LR, Lucas J, Chaudhary I, Dehnhardt C, Santos ED, Chen Z, dos Santos O, Ayral-Kaloustian S, Venkatesan A, Hollander I. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res. 2011 May 15;17(10):3193-203. doi: 10.1158/1078-0432.CCR-10-1694. Epub 2011 Feb 15. PMID: 21325073.

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1: 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. PubMed PMID: 31822716; PubMed Central PMCID: PMC6904563.

2: Song W, Tweed JA, Visswanathan R, Saunders JP, Gu Z, Holliman CL. Bioanalysis of Targeted Nanoparticles in Monkey Plasma via LC-MS/MS. Anal Chem. 2019 Nov 5;91(21):13874-13882. doi: 10.1021/acs.analchem.9b03367. Epub 2019 Oct 17. PubMed PMID: 31584812.

3: Lee TD, Lee OW, Brimacombe KR, Chen L, Guha R, Lusvarghi S, Tebase BG, Klumpp-Thomas C, Robey RW, Ambudkar SV, Shen M, Gottesman MM, Hall MD. A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein. Mol Pharmacol. 2019 Nov;96(5):629-640. doi: 10.1124/mol.119.115964. Epub 2019 Sep 12. PubMed PMID: 31515284; PubMed Central PMCID: PMC6790066.

4: Houk BE, Alvey CW, Visswanathan R, Kirkovsky L, Matschke KT, Kimoto E, Ryder T, Obach RS, Durairaj C. Distribution, Metabolism, and Excretion of Gedatolisib in Healthy Male Volunteers After a Single Intravenous Infusion. Clin Pharmacol Drug Dev. 2019 Jan;8(1):22-31. doi: 10.1002/cpdd.615. Epub 2018 Sep 26. PubMed PMID: 30256541.

5: Sima N, Sun W, Gorshkov K, Shen M, Huang W, Zhu W, Xie X, Zheng W, Cheng X. Small Molecules Identified from a Quantitative Drug Combinational Screen Resensitize Cisplatin's Response in Drug-Resistant Ovarian Cancer Cells. Transl Oncol. 2018 Aug;11(4):1053-1064. doi: 10.1016/j.tranon.2018.06.002. Epub 2018 Jul 5. PubMed PMID: 29982103; PubMed Central PMCID: PMC6034569.

6: Park YL, Kim HP, Cho YW, Min DW, Cheon SK, Lim YJ, Song SH, Kim SJ, Han SW, Park KJ, Kim TY. Activation of WNT/β-catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations. Int J Cancer. 2019 Jan 15;144(2):389-401. doi: 10.1002/ijc.31662. Epub 2018 Nov 29. PubMed PMID: 29978469; PubMed Central PMCID: PMC6587482.

7: Shah K, Moharram SA, Kazi JU. Acute leukemia cells resistant to PI3K/mTOR inhibition display upregulation of P2RY14 expression. Clin Epigenetics. 2018 Jun 19;10:83. doi: 10.1186/s13148-018-0516-x. eCollection 2018. PubMed PMID: 29951132; PubMed Central PMCID: PMC6010022.

8: Aldaregia J, Odriozola A, Matheu A, Garcia I. Targeting mTOR as a Therapeutic Approach in Medulloblastoma. Int J Mol Sci. 2018 Jun 22;19(7). pii: E1838. doi: 10.3390/ijms19071838. Review. PubMed PMID: 29932116; PubMed Central PMCID: PMC6073374.

9: Makinoshima H, Umemura S, Suzuki A, Nakanishi H, Maruyama A, Udagawa H, Mimaki S, Matsumoto S, Niho S, Ishii G, Tsuboi M, Ochiai A, Esumi H, Sasaki T, Goto K, Tsuchihara K. Metabolic Determinants of Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitor in Small-Cell Lung Carcinoma. Cancer Res. 2018 May 1;78(9):2179-2190. doi: 10.1158/0008-5472.CAN-17-2109. Epub 2018 Feb 28. PubMed PMID: 29490947.

10: 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. eCollection 2017 Oct 17. PubMed PMID: 29156674; PubMed Central PMCID: PMC5689564.

11: 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. PubMed PMID: 29067643; PubMed Central PMCID: PMC5700209.

12: Ciuffreda L, Del Curatolo A, Falcone I, Conciatori F, Bazzichetto C, Cognetti F, Corbo V, Scarpa A, Milella M. Lack of growth inhibitory synergism with combined MAPK/PI3K inhibition in preclinical models of pancreatic cancer. Ann Oncol. 2017 Nov 1;28(11):2896-2898. doi: 10.1093/annonc/mdx335. PubMed PMID: 28666315.

13: Vilchez V, Turcios L, Butterfield DA, Mitov MI, Coquillard CL, Brandon JA, Cornea V, Gedaly R, Marti F. Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice. Transpl Int. 2017 Oct;30(10):1061-1074. doi: 10.1111/tri.12989. Epub 2017 Jul 31. PubMed PMID: 28543637.

14: Gazi M, Moharram SA, Marhäll A, Kazi JU. The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell acute lymphoblastic leukemia (T-ALL). Cancer Lett. 2017 Apr 28;392:9-16. doi: 10.1016/j.canlet.2017.01.035. Epub 2017 Feb 1. Erratum in: Cancer Lett. 2019 Oct 1;461:155. PubMed PMID: 28159681.

15: Tasian SK, Teachey DT, Li Y, Shen F, Harvey RC, Chen IM, Ryan T, Vincent TL, Willman CL, Perl AE, Hunger SP, Loh ML, Carroll M, Grupp SA. Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 2017 Jan 12;129(2):177-187. doi: 10.1182/blood-2016-05-707653. Epub 2016 Oct 24. PubMed PMID: 27777238; PubMed Central PMCID: PMC5234216.

16: Iezzi A, Caiola E, Broggini M. Activity of Pan-Class I Isoform PI3K/mTOR Inhibitor PF-05212384 in Combination with Crizotinib in Ovarian Cancer Xenografts and PDX. Transl Oncol. 2016 Oct;9(5):458-465. doi: 10.1016/j.tranon.2016.08.011. PubMed PMID: 27751351; PubMed Central PMCID: PMC5067927.

17: Freitag H, Christen F, Lewens F, Grass I, Briest F, Iwaszkiewicz S, Siegmund B, Grabowski P. Inhibition of mTOR's Catalytic Site by PKI-587 Is a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease. Neuroendocrinology. 2017;105(1):90-104. doi: 10.1159/000448843. Epub 2016 Aug 12. PubMed PMID: 27513674; PubMed Central PMCID: PMC5475233.

18: Del Campo JM, Birrer M, Davis C, Fujiwara K, Gollerkeri A, Gore M, Houk B, Lau S, Poveda A, González-Martín A, Muller C, Muro K, Pierce K, Suzuki M, Vermette J, Oza A. A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer. Gynecol Oncol. 2016 Jul;142(1):62-69. doi: 10.1016/j.ygyno.2016.04.019. Epub 2016 Apr 24. PubMed PMID: 27103175.

19: Lindblad O, Cordero E, Puissant A, Macaulay L, Ramos A, Kabir NN, Sun J, Vallon-Christersson J, Haraldsson K, Hemann MT, Borg Å, Levander F, Stegmaier K, Pietras K, Rönnstrand L, Kazi JU. Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML. Oncogene. 2016 Sep 29;35(39):5119-31. doi: 10.1038/onc.2016.41. Epub 2016 Mar 21. PubMed PMID: 26999641; PubMed Central PMCID: PMC5399143.

20: Takeda T, Wang Y, Bryant SH. Structural insights of a PI3K/mTOR dual inhibitor with the morpholino-triazine scaffold. J Comput Aided Mol Des. 2016 Apr;30(4):323-30. doi: 10.1007/s10822-016-9905-4. Epub 2016 Mar 8. PubMed PMID: 26956874; PubMed Central PMCID: PMC4833818.