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RO4929097 – TARGETING NOTCH SIGNALING IN CANCER

RO4929097: INHIBIT GAMMA SECRETASE:

Gamma secretase is famous protease consists of several subunits complex. This enzyme is also recognized as inter-membrane protease as it cuts trans-membrane proteins. The most eminent gamma secretase example is breakage of amyloid precursor, a protein to produce amyloid beta peptide which is involved in the formation of amyloid plaques in patient’s brain who suffer with Alzheimer’s disease. In the present situation though, we concentrate on the key role of gamma secretase in the Notch protein processing. It has been found as there is link between anomalous notch signaling and many cancers. Hence the idea of targeting those enzymes which are responsible for the processing of Notch protein became the reason of RO4929097 gamma secretase inhibitor discovery. The inhibiting Notch signaling by using RO4929097 GS inhibitor has been confirmed by protein estimation methods like Biuret method etc.

RO4929097 Chemical Structure

 

The RO4929097 structure is characterized in a good way which is a small-molecule and is orally bio-available. A 4 nM concentration of RO4929097 IC50 was used for a strong gamma secretase. The tumor proliferation was reduced when RO4929097 bound with GS in order to hinder the Notch receptors activity. Although RO4929097 does not bring on apoptosis or hinder proliferation of tumor cells, it is able to produce slow-growing and less transformed phenotype in cancer cells. Mostly RO4929097 price is very high; you can buy RO4929097 by investing about $300 for a vial of 5 mg. This can be taken from any RO4929097 supplier. RO4929097 solubility is still under debate. RO4929097 stability can be assured under low temperature (-20℃).

 

TRIALS OF RO4929097:

The amount of unbound RO4929097 present in human plasma has been done by the use of reversed-phased liquid chromatography (LC) along with method of tandem mass spectrometry (MS). The knowledge gained for this assessment was critical for the evaluation of pharmacokinetics in patients having cancer [1].

In Notch signaling, aberrations are often seen in case of tumor development and melanoma tumorigenesis. Both in vitro and in vivo studies have been done on xenograft systems, the activity of RO4929097 are reported on the stem cells and different melanoma cells. RO4929097 was observed to decrease HES1 protein levels, regulated by Notch, along with decreased proliferation and distorted ability of these cells to form colonies on agar. RO4929097 not only decreased the tumor size and but also its invasive potential in different xenografts [2]. The similar action on Notch was also analyzed in case of cell lines of T-cell acute lymphoblastic leukemia (T-ALL) [3]. When intermittent dosage of RO4929097 was used a decrease in expression of Hes1 gene was observed which is angiogenesis related and Not regulated [4]. Although those tumors which have high expression of IL6 and IL8, the effectiveness of RO4929097 was limited. This led to the need of patients profiling to choose those having low levels of IL6 and IL8 for RO4929097 treatment [5].

 

CLINICAL EVALUATION OF RO4929097:

Patients having melanoma, neuroendocrine, ovarian cancers and sarcoma, RO4929097 treatment were effective with fine tolerance providing an extended stable disease although the preclinical trials of IL-6 and IL-8 were predictive markers of adaptive treatment with RO4929097. And phase I and Phase II RO4929097 clinical trial were acceptable for that [6]. RO4929097 also gained fame in case of pediatric cancer in vivo experiments and also found to be good in case of osteosarcoma, solid tumors and acute lymphoblastic leukemia (ALL) xenografts treatment [7].

National Cancer Institute (NCI) also reported the side effects as well as tolerance of RO4929097 during phase II trials in patients suffering with metastatic epithelial ovarian cancer, fallopian tube cancer (NCT01175343) and platinum resistant recurrent. They also analyzed the efficiency of RO4929097 while tested on multiple myeloma during phase II trials after transplantation of autologous stem cell (NCT01251172). While dose pharmacokinetics, pharmacodynamics studies and safety profile of RO4929097 was done in patients suffering with metastatic solid malignant tumors (NCT01096355). Roche has also checked it performance on refractory or recurrent non-small cell lung cancer (NSCLC) patients (NCT01070927).

 

 

REFERENCES:

1. Wu J, e.a., Validation and implementation of a liquid chromatography/tandem mass spectrometry assay for quantitation of the total and unbound RO4929097, a γ-secretase inhibitor targeting Notch signaling, in human plasma. Journal of Chromatography B, 2011.

2. Huynh C, e.a., The Novel Gamma Secretase Inhibitor RO4929097 Reduces the Tumor Initiating Potential of Melanoma. PLoS ONE, 2011.

3. Wei P, e.a., Evaluation of Selective γ-Secretase Inhibitor PF-03084014 for Its Antitumor Efficacy and Gastrointestinal Safety to Guide Optimal Clinical Trial Design. Mol Cancer Ther, 2010.

4. Luistro L, e.a., Preclinical Profile of a Potent γ-Secretase Inhibitor Targeting Notch Signaling with In vivo Efficacy and Pharmacodynamic Properties. Cancer Res, 2009.

5. He W, e.a., High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the γ-secretase inhibitor, RO4929097. Molecular Oncology, 2011.

6. Tolcher AW, e.a., A phase I study of RO4929097, a novel gamma secretase inhibitor, in patients with advanced solid tumors. J Clin Oncol, 2010.

7. Kolb EA, e.a., Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a γ-secretase inhibitor targeting notch signaling. Pediatric Blood & Cancer, 2011.

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S1575 RO4929097 RO4929097 (RG-4733) is a γ secretase inhibitor with IC50 of 4 nM in a cell-free assay, inhibiting cellular processing of Aβ40 and Notch with EC50 of 14 nM and 5 nM, respectively. Phase 2. (101) (7)

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