PERIFOSINE, A NOVEL AKT INHIBITOR

by Selleckchem | Sep 20 2012

PERIFOSINE
Perifosine, also called D-21266 or KRX-0401, is identified as a heterocyclic alkylphospholipid and a drug candidate being developed for a variety of cancers. Perifosine is an orally active ark inhibitor which is completely bioavailable with antitumor capacities. Perifosine has displayed significant anti-proliferative and pro-apoptosis activity in vitro in vitro and in vivo, and now is currently being tested in different clinical trials.

MECHANISM OF PERIFOSINE ACTION

Lipid rafts, also identified as lipid microdomains of the plasma membrane, are found to be key mediators of alkylphospholipid-induced apoptosis. By targeting cellular membranes, perifosine involves in the modulation of membrane permeability, membrane lipid composition, phospholipid metabolism, and mitogenic signal transduction, and further results in cell differentiation and inhibition of cell growth. More specially, Perifosine primarily interferes with lipid microdomains of the plasma membrane called lipid rafts of proliferating cells with no or minimal effects on normal cells. Since lipid rafts serve as organizing centers for the assembly of signaling molecules, and involves in membrane fluidity and membrane protein trafficking and regulation of neurotransmission and receptor trafficking. Thus, Perifosine modulates a variety of signal pathways originating from the cell membrane. For example, Perifosine regulates the cell cycle through cdk2 [1], induces cell apoptosis by SAPK/Jnk pathway [2] and inhibits cell proliferation by MAPK pathway [3]. Besides, Perifosine also involves in the synthesis regulation of membrane lipid, such as phosphatidylcholine [4].

CLINICAL TRIALS
Currently, perifosine has been evaluated as an anti-cancer agent in phase I and II clinical trials, and shows effective therapy results. According to the known study, perifosine has been involved in the clinical trials of multiple types of advanced cancers, including Pediatric Solid Tumors, renal cell carcinoma (RCC), Pancreatic Cancer, Carcinoma of the Kidney and Carcinoma of the Kidney. Clinical data shows that perifosine treatment is well tolerated, induces dose-dependent pathway inhibition in tissues, and results in anti-tumor activity even in patients with refractory and relapsed cancers. The main parameters, such as efficacy, safety, pharmacokinetics and pharmacodynamics, has also been evaluated or being evaluated. Besides the monotherapy, combination study of perifosine and other drugs, such as Lenalidomide, Sorafenib, or Imatinib Mesylate is being evaluated under clinical phase I/II trials in Leukemia or locally advanced solid tumors. Moreover, perifosine is also used in Phase II Trial in patients with Recurrent Prostate Cancer after failure of other drug therapy. We will continue to follow up on the new clinical studies about perifosine and the related combination therapy.

REFERENCES
[1]. Momota H, et al. Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res. 2005, 65(16), 7429-7435.
[2]. Ruiter GA, et al. Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis. Cancer Res. 1999, 59(10), 2457-2463.
[3]. Block M, et al. Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells. Int J Oncol. 2012, doi: 10.3892/ijo.2012.1591.
[4]. van der Luit AH, et al. A new class of anticancer alkylphospholipids uses lipid rafts as membrane gateways to induce apoptosis in lymphoma cells. Mol Cancer Ther. 2007, 6(8), 2337-2345.

Cat.No.	Product Name	Information
S1037	Perifosine	Perifosine is a novel Akt inhibitor with IC50 of 4.7 μM in MM.1S cells, targets pleckstrin homology domain of Akt. Phase 3.
S1029	Lenalidomide	Lenalidomide is a TNF-α secretion inhibitor with IC50 of 13 nM in PBMCs. Lenalidomide (CC-5013) is a ligand of ubiquitin E3 ligase cereblon (CRBN), and it causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. Lenalidomide promotes cleaved caspase-3 expression and inhibit VEGF expression and induces apoptosis.
S1040	Sorafenib tosylate	Sorafenib tosylate is a multikinase inhibitor of Raf-1 and B-Raf with IC50 of 6 nM and 22 nM in cell-free assays, respectively. Sorafenib Tosylate inhibits VEGFR-2, VEGFR-3, PDGFR-β, Flt-3 and c-KIT with IC50 of 90 nM, 20 nM, 57 nM, 59 nM and 68 nM, respectively. Sorafenib Tosylate induces autophagy and apoptosis and activates ferroptosis with anti-tumor activity.
S1026	Imatinib Mesylate	Imatinib Mesylate is an orally bioavailability mesylate salt of Imatinib, which is a multi-target inhibitor of v-Abl, c-Kit and PDGFR with IC50 of 0.6 μM, 0.1 μM and 0.1 μM in cell-free or cell-based assays, respectively. Imatinib Mesylate (STI571) induces autophagy.