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  Palomid 529

Palomid 529 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 2008;68(22):9551–7]

Current developer: Paloma Pharmaceuticals.

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 Company’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 Institute’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.).

1: 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. Epub 2011 Oct 29. PubMed PMID: 22100549.

2: 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.

3: 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. Epub 2011 Jan 17. PubMed PMID: 21242970; PubMed Central PMCID: PMC3107712.

4: 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. Epub 2009 Apr 15. PubMed PMID: 19369237.

5: 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. Epub 2009 Feb 24. PubMed PMID: 19240717; PubMed Central PMCID: PMC2661786.

6: 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. PubMed PMID: 19010932; PubMed Central PMCID: PMC2727940.