Drugs in Clinical Pipeline: Salirasib

Salirasib [2-(((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)thio)benzoic acid] is an isoprenoid with farnesyl (C15) chain-length that interferes with Ras membrane interactions which are crucial for Ras-dependent transformation. Salirasib was designed to mimic the farnesyl moiety in the carboxy terminal of Ras and was found to induce accelerated dislodgement of Ras from the cell membrane and subsequent degradation of the protein. Biochemical and gene expression profiling experiments provided strong support to the notion that the growth inhibitory effects of FTS are the result of inhibition of Ras-dependent signaling. Ras proteins, which are found in many cancer types, contribute to malignancy and are therefore considered favored targets for directed therapy.

Though developed as Ras inhibitor, Salirasib, a S-prenyl-cysteine analog that has been shown to block Ras and/or mTOR activation in several non hepatic tumor cell lines.

Salirasib inhibits the growth of human Ha-ras-transformed Rat1 fibroblasts with an IC₅₀ value of 7.5 µM [1]. In in vitro growth inhibition assays using a cancer cell lines, Panc-1 (that harbors an oncogenic K-Ras),  and U87 glioblastoma cell line in which Ras is not mutated but is chronically active due to high activity of growth factor receptors, Salirasib showed good Ras inhibition potency with IC₅₀ of  35, 50 uM, respectively [2].

The activity of Salirasib is as follows:

IC₅₀ (Pan-1 Cell Line) = 30 uM

IC₅₀ (U87 Cell Line) = 50 uM

Common Name: Salirasib

Synonyms:  FTS; S-trans-trans-farnesylthiosalicylic acid

IUPAC Name: 2-(((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)thio)benzoic acid

CAS Number: 162520-00-5

SMILES: C/C(=C\CSc1ccccc1C(=O)O)/CC/C=C(\C)/CCC=C(C)C

Mechanism of Action: Ras Inhibitor

Indication: Various Cancers

Development Stage: Phase II

Company: Concordia Pharmaceuticals

Eidogen Sertanty Inc Provides Oncology Knowledge Base (OKB): a Collection of Various Cancer Targets and Their Inhibitors.

Animal studies demonstrated that Salirasib inhibited tumor growth, downregulated gene expression in the cell cycle and Ras signaling pathways. In a clinical study of Salirasib combined with standard doses of Gemcitabine, it was demonstrated that the two drugs have no overlapping pharmacokinetics. Salirasib recommended dose was 600 mg twice daily and the progression-free survival was 4.7 months. Future studies will determine whether Salirasib adds to the anti-tumor activity of drugs approved by the US FDA for pancreatic cancer [3].

Salirasib induced a time and dose dependent growth inhibition in hepatocarcinoma cells through inhibition of proliferation and partially through induction of apoptosis. A 50 percent reduction in cell growth was obtained in all three human hepatoma cell lines (HepG2, Huh7, and Hep3B) at a dose of 150 µM when they were cultured with serum. By contrast, Salirasib was more potent at reducing cell growth after stimulation with EGF or IGF2 under serum-free conditions, with an IC₅₀ ranging from 60 µM to 85 µM. The drug-induced anti-proliferative effect was associated with downregulation of cyclin A and to a lesser extent of cyclin D1, and upregulation of p21 and p27. Apoptosis induction was related to a global pro-apoptotic balance with caspase 3 activation, cytochrome c release, death receptor upregulation, and a reduced mRNA expression of the apoptosis inhibitors cFLIP and survivin. These effects were associated with ras downregulation and mTOR inhibition, without reduction of ERK and Akt activation. In vivo, Salirasib reduced tumour growth from day 5 onwards. After 12 days of treatment, mean tumor weight was diminished by 56 percent in the treated animals [4].

In a Phase II study to determine the activity of Salirasib in patients with advanced lung adenocarcinomas with KRAS mutations, the results suggest that Salirasib at the studied dose and schedule has insufficient activity in the treatment of KRAS mutant lung adenocarcinoma to warrant further evaluation [5].

Salirasib sensitizes hepatocarcinoma cells (HCC) to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis by a mechanism involving the DR5 receptor and survivin inhibition. Results show that pretreatment with Salirasib sensitized human hepatocarcinoma cell lines, but not normal human hepatocytes, to TRAIL-induced apoptosis. Survivin inhibition had an important role in this process and was sufficient to sensitize hepatocarcinoma cells to apoptosis. Furthermore, TRAIL-induced apoptosis in HCC cells pretreated with salirasib was dependent on activation of death receptor-DR5. These results in human hepatocarcinoma cell lines and primary hepatocytes provide a rationale for testing the combination of salirasib and TRAIL agonists in human hepatocarcinoma [6].

References:

1. Marciano, D.; et. al. Farnesyl derivatives of rigid carboxylic acids inhibitors of ras-dependent cell growth. J Med Chem 1995, 38(8), 1267-1272.

2. Goldberg, L.; et. al. New derivatives of farnesylthiosalicylic acid (salirasib) for cancer treatment: farnesylthiosalicylamide inhibits tumor growth in nude mice models. J Med Chem 2009, 52(1), 197-205.
3. Bustinza-Linares, E.; et. al. Salirasib in the treatment of pancreatic cancer. Future Oncol 2010, 6(6), 885-891.
4. Charette, N.; et. al. Salirasib inhibits the growth of hepatocarcinoma cell lines in vitro and tumor growth in vivo through ras and mTOR inhibition. Mol Cancer 2010, 9, 256.
5. Riely, G. J.; et. al. A phase II trial of Salirasib in patients with lung adenocarcinomas with KRAS mutations. J Thorac Oncol 2011, 6(8), 1435-1437.
6. Starkel, P.; et. al. Salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis through DR5 and survivin-dependent mechanisms. Cell Death and Disease 2013, 4, e471.