Palomid-529

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

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).

Price and Availability

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Chemical Structure

Theoretical Analysis

MedKoo Cat#: 202133Name: Palomid-529CAS#: 914913-88-5Chemical Formula: C24H22O6Exact Mass: 406.14164Molecular Weight: 406.42788Elemental Analysis:C, 70.92; H, 5.46; O, 23.62

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

Technical Data

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.).   

References

1: He TY, Tsai LH, Huang CC, Chou MC, Lee H. LKB1Loss at Transcriptional Level Promotes Tumor Malignancy and Poor PatientOutcomes in Colorectal Cancer. Ann Surg Oncol. 2014 May 31. [Epub aheadof 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-mediatedsurvivin function and delaying DNA repair in prostate cancer models.Prostate. 2014 Jun;74(8):852-68. doi: 10.1002/pros.22804. Epub 2014 Apr8. 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 thetreatment of neovascular age-related macular degeneration. Graefes ArchClin 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 mTORC1and mTORC2 inhibitor Palomid 529 penetrates the blood-brain barrierwithout restriction by ABCB1 and ABCG2. Int J Cancer. 2013 Sep1;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 signalingwith a novel dual TORC1/2 inhibitor. Am J Pathol. 2012Nov;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-performanceliquid chromatography analysis of a novel small-molecule, anti-cancerdrug, Palomid 529, in human and mouse plasma and in mouse tissuehomogenates. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Dec15;879(32):3823-31. doi: 10.1016/j.jchromb.2011.10.028. Epub 2011 Oct29. 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 inaggressive and hormone-refractory prostate cancer cells. Endocr RelatCancer. 2011 Jul 1;18(4):385-400. doi: 10.1530/ERC-11-0045. Print 2011Aug. PubMed PMID: 21551258.

8: Xiang T, Jia Y, Sherris D, Li S, Wang H, Lu D, Yang Q. Targeting theAkt/mTOR pathway in Brca1-deficient cancers. Oncogene. 2011 May26;30(21):2443-50. doi: 10.1038/onc.2010.603. Epub 2011 Jan 17. PubMedPMID: 21242970; PubMed Central PMCID: PMC3107712.

9: Lewis GP, Chapin EA, Byun J, Luna G, Sherris D, Fisher SK. Mullercell reactivity and photoreceptor cell death are reduced afterexperimental retinal detachment using an inhibitor of the Akt/mTORpathway. 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 Aktinhibitor Palomid 529 (P529) enhances the effect of radiotherapy inprostate cancer. Br J Cancer. 2009 Mar 24;100(6):932-40. doi:10.1038/sj.bjc.6604938. Epub 2009 Feb 24. PubMed PMID: 19240717; PubMedCentral 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 inhibitorthat reduces tumor growth, tumor angiogenesis, and vascularpermeability. Cancer Res. 2008 Nov 15;68(22):9551-7. doi:10.1158/0008-5472.CAN-08-2058. PubMed PMID: 19010932; PubMed CentralPMCID: PMC2727940.