Palomid-529
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MedKoo CAT#: 202133

CAS#: 914913-88-5

Description: Palomid 529, also known as P529, is a novel PI3K/Akt/mTOR inhibitor. Palomid 529 (P529) inhibits the TORC1 and TORC2 complexes and shows both inhibition of Akt signaling and mTOR signaling similarly in tumor and vasculature. It was demonstrated that P529 inhibited tumor growth, angiogenesis, and vascular permeability. It retained the beneficial aspects of tumor vascular normalization that rapamycin boasts. However, P529 showed the additional benefit of blocking pAktS473 signaling consistent with blocking TORC2 in all cells and thus bypassing feedback loops that lead to increased Akt signaling in some tumor cells. (Source: Cancer Res 008;68(22):9551–7).


Chemical Structure

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Palomid-529
CAS# 914913-88-5

Theoretical Analysis

MedKoo Cat#: 202133
Name: Palomid-529
CAS#: 914913-88-5
Chemical Formula: C24H22O6
Exact Mass: 406.14164
Molecular Weight: 406.43
Elemental Analysis: C, 70.92; H, 5.46; O, 23.62

Price and Availability

Size Price Availability Quantity
10.0mg USD 150.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 750.0 Ready to ship
200.0mg USD 1350.0 Ready to ship
500.0mg USD 1950.0 Ready to ship
1.0g USD 2850.0 2 Weeks
2.0g USD 4650.0 2 Weeks
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Synonym: Palomid 529; Palomid-529; Palomid529; P529; P 529; P-529.

IUPAC/Chemical Name: 8-(1-hydroxyethyl)-2-methoxy-3-((4-methoxybenzyl)oxy)-6H-benzo[c]chromen-6-one

InChi Key: YEAHTLOYHVWAKW-UHFFFAOYSA-N

InChi Code: InChI=1S/C24H22O6/c1-14(25)16-6-9-18-19-11-22(28-3)23(12-21(19)30-24(26)20(18)10-16)29-13-15-4-7-17(27-2)8-5-15/h4-12,14,25H,13H2,1-3H3

SMILES Code: O=C1C2=CC(C(O)C)=CC=C2C3=C(O1)C=C(OCC4=CC=C(OC)C=C4)C(OC)=C3

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

Biological target: Palomid 529 is an inhibitor of mTORC1 and mTORC2 complexes.
In vitro activity: The potential effect of Palomid 529 on cell proliferation was analyzed. BrdU incorporation ELISA assay was performed, and results show that Palomid 529 dose-dependently inhibited 786-O cell proliferation (Fig. 1C). Apoptosis activation could be a primary mechanism of viability reduction and/or proliferation inhibition. As shown in Fig. 1D, Palomid 529 at 1-10 μM significantly increased the Histone-bound DNA ELISA OD, suggesting apoptosis activation. Additionally, the percentage of apoptotic nuclei was increased in Palomid 529 (1-10 μM)-treated 786-O cells (Fig. 1E). Palomid 529 also induced cleavages of both PARP (Poly (ADP-ribose) polymerases) and caspase-9 in 786-O cells (Fig. 1F). Palomid 529 at 0.1 μM had no significant effect on cell apoptosis (Fig. 1D-F). Together, these results demonstrate that Palomid 529 exerts cytotoxic, anti-proliferative and pro-apoptotic activities in 786-O cells. Reference: Cell Physiol Biochem. 2018;50(2):640-653. https://www.karger.com/Article/FullText/494185
In vivo activity: The potential effect of Palomid 529 in vivo was tested. 786-O cells (5×106 cells per mouse) were inoculated via s.c. injection to the severe combined immunodeficiency (SCID) mice. Tumor growth curve results show that Palomid 529 (100 mg/kg/2 d, i.p., for 18 days) administration significantly inhibited 786-O xenograft tumor growth in SCID mice (Fig. 7A). The estimated daily tumor growth was calculated by: (tumor volume at Day-42— tumor volume at Day-0)/42. Results show again that Palomid 529 administration inhibited 786-O xenograft tumor growth. At Day-42, the tumors in Palomid 529 treatment group were significantly lighter than the vehicle control tumors (Fig. 7C). Reference: Cell Physiol Biochem. 2018;50(2):640-653. https://www.karger.com/Article/FullText/494185

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 10.0 24.6

Preparing Stock Solutions

The following data is based on the product molecular weight 406.43 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. Xing ZY, Wang Y, Cheng L, Chen J, He XZ, Xing W. Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo. Cell Physiol Biochem. 2018;50(2):640-653. doi: 10.1159/000494185. Epub 2018 Oct 11. PMID: 30308518.
In vitro protocol: 1. Xing ZY, Wang Y, Cheng L, Chen J, He XZ, Xing W. Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo. Cell Physiol Biochem. 2018;50(2):640-653. doi: 10.1159/000494185. Epub 2018 Oct 11. PMID: 30308518.
In vivo protocol: 1. Xing ZY, Wang Y, Cheng L, Chen J, He XZ, Xing W. Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo. Cell Physiol Biochem. 2018;50(2):640-653. doi: 10.1159/000494185. Epub 2018 Oct 11. PMID: 30308518.

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1: He TY, Tsai LH, Huang CC, Chou MC, Lee H. LKB1 Loss at Transcriptional Level Promotes Tumor Malignancy and Poor Patient Outcomes in Colorectal Cancer. Ann Surg Oncol. 2014 May 31. [Epub ahead of print] PubMed PMID: 24879590.

2: Gravina GL, Marampon F, Sherris D, Vittorini F, Di Cesare E, Tombolini V, Lenzi A, Jannini EA, Festuccia C. Torc1/Torc2 inhibitor, Palomid 529, enhances radiation response modulating CRM1-mediated survivin function and delaying DNA repair in prostate cancer models. Prostate. 2014 Jun;74(8):852-68. doi: 10.1002/pros.22804. Epub 2014 Apr 8. PubMed PMID: 24715588.

3: Dalal M, Jacobs-El N, Nicholson B, Tuo J, Chew E, Chan CC, Nussenblatt R, Ferris F, Meyerle C. Subconjunctival Palomid 529 in the treatment of neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2013 Dec;251(12):2705-9. doi: 10.1007/s00417-013-2375-7. Epub 2013 May 21. PubMed PMID: 23689994.

4: Lin F, Buil L, Sherris D, Beijnen JH, van Tellingen O. Dual mTORC1 and mTORC2 inhibitor Palomid 529 penetrates the blood-brain barrier without restriction by ABCB1 and ABCG2. Int J Cancer. 2013 Sep 1;133(5):1222-33. doi: 10.1002/ijc.28126. Epub 2013 Apr 1. PubMed PMID: 23436212.

5: Syed F, Sherris D, Paus R, Varmeh S, Singh S, Pandolfi PP, Bayat A. Keloid disease can be inhibited by antagonizing excessive mTOR signaling with a novel dual TORC1/2 inhibitor. Am J Pathol. 2012 Nov;181(5):1642-58. doi: 10.1016/j.ajpath.2012.08.006. Epub 2012 Sep 11. Erratum in: Am J Pathol. 2014 Apr;184(4):1253. Singh, Subir [added]. PubMed PMID: 22982188.

6: Lin F, Sherris D, Beijnen JH, Van Tellingen O. High-performance liquid chromatography analysis of a novel small-molecule, anti-cancer drug, Palomid 529, in human and mouse plasma and in mouse tissue homogenates. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Dec 15;879(32):3823-31. doi: 10.1016/j.jchromb.2011.10.028. Epub 2011 Oct 29. PubMed PMID: 22100549.

7: Gravina GL, Marampon F, Petini F, Biordi L, Sherris D, Jannini EA, Tombolini V, Festuccia C. The TORC1/TORC2 inhibitor, Palomid 529, reduces tumor growth and sensitizes to docetaxel and cisplatin in aggressive and hormone-refractory prostate cancer cells. Endocr Relat Cancer. 2011 Jul 1;18(4):385-400. doi: 10.1530/ERC-11-0045. Print 2011 Aug. PubMed PMID: 21551258.

8: Xiang T, Jia Y, Sherris D, Li S, Wang H, Lu D, Yang Q. Targeting the Akt/mTOR pathway in Brca1-deficient cancers. Oncogene. 2011 May 26;30(21):2443-50. doi: 10.1038/onc.2010.603. Epub 2011 Jan 17. PubMed PMID: 21242970; PubMed Central PMCID: PMC3107712.

9: Lewis GP, Chapin EA, Byun J, Luna G, Sherris D, Fisher SK. Muller cell reactivity and photoreceptor cell death are reduced after experimental retinal detachment using an inhibitor of the Akt/mTOR pathway. Invest Ophthalmol Vis Sci. 2009 Sep;50(9):4429-35. doi: 10.1167/iovs.09-3445. Epub 2009 Apr 15. PubMed PMID: 19369237.

10: Diaz R, Nguewa PA, Diaz-Gonzalez JA, Hamel E, Gonzalez-Moreno O, Catena R, Serrano D, Redrado M, Sherris D, Calvo A. The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer. Br J Cancer. 2009 Mar 24;100(6):932-40. doi: 10.1038/sj.bjc.6604938. Epub 2009 Feb 24. PubMed PMID: 19240717; PubMed Central PMCID: PMC2661786.

11: Xue Q, Hopkins B, Perruzzi C, Udayakumar D, Sherris D, Benjamin LE. Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability. Cancer Res. 2008 Nov 15;68(22):9551-7. doi: 10.1158/0008-5472.CAN-08-2058. PubMed PMID: 19010932; PubMed Central PMCID: PMC2727940.



Additional Information

 
Phase I trial using Palomid 529. In May, 2011, Paloma Pharmaceuticals accouned that its  first-in-class allosteric dual TORC1/TORC2 dissociative inhibitor Palomid 529  has successfully completed the CompanyÂ’s first three cohorts of its Phase I intravitreal administration trial in patients with age-related macular degeneration (AMD). In addition, the National Eye Institute has treated its first patient in the InstituteÂ’s own Phase I AMD trial administering P529 subconjunctival, “A Phase I Unmasked Study to Investigate the Safety and Tolerability of Subconjunctival Injections of Palomid 529 in Patients With Neovascular Age-Related Macular Degeneration.” Both clinical trials have shown preliminary activity.
 
Palomid 529 reduces tumor growth, tumor angiogenesis, and vascular permeability. Palomid 529 (P529), which inhibits the TORC1 and TORC2 complexes and shows both inhibition of Akt signaling and mTOR signaling similarly in tumor and vasculature. We show that P529 inhibits tumor growth, angiogenesis, and vascular permeability. It retains the beneficial aspects of tumor vascular normalization that rapamycin boasts. However, P529 has the additional benefit of blocking pAktS473 signaling consistent with blocking TORC2 in all cells and thus bypassing feedback loops that lead to increased Akt signaling in some tumor cells. (source: Cancer Res. 2008 Nov 15;68(22):9551-7).
 
Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer. P529 showed a potent antiproliferative activity in the NCI-60 cell lines panel, with growth inhibitory 50 (GI50) <35 microM. In addition, P529 significantly enhanced the antiproliferative effect of radiation in prostate cancer cells (PC-3). Analysis of signalling pathways targeted by P529 exhibited a decrease in p-Akt, VEGF, MMP-2, MMP-9, and Id-1 levels after radiation treatment. Moreover, the Bcl-2/Bax ratio was also reduced. Treatment of PC-3 tumour-bearing mice with 20 mg kg(-1) P529 or 6 Gy radiation dose decreased tumour size by 42.9 and 53%, respectively. Combination of both treatments resulted in 77.4% tumour shrinkage. Decreased tumour growth was due to reduced proliferation and increased apoptosis (as assessed by PCNA and caspase-3 immunostaining). Our results show the antitumour efficacy of P529 alone, and as a radiosensitiser, and suggest that this compound could be used in the future to treat human prostate cancer. (source: Br J Cancer. 2009 Mar 24;100(6):932-40 . Epub 2009 Feb 24.).