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RO4929097 – CHECKS NOTCH SIGNALING IN CANCERS

RO4929097: A GAMMA SECRETASE INHIBITOR:

Among well known proteases Gamma secretase is one which is made up of various subunits. This is present in the membrane hence is a protein in membrane which is also capable of cleaving certain transmembrane proteins therefore also known as the intramembrane protease. In case of Alzheimer’s disease amyloid plaques are formed in brain, these plaques are resulted due to the amyloid beta peptide and these peptides are produced due to the action of gamma secretase, this is one of the well known examples of this protease. Presently, we are focusing on the important role of gamma secretase in the Notch protein processing. In case of many cancers and tumors this Notch protein signaling is found to be abnormal, therefore the arresting of this pathway can be an authentic way to get rid of abnormal cell growth. In the light of this idea a novel RO4929097 gamma secretase inhibitor is discovered. The inhibitory effect of this inhibitor has been confirmed by various methods like western blotting.

RO4929097 Chemical Structure

RO4929097 is an orally bioavailable little molecule and the RO4929097 structure has also characterized. A 4 nM of RO4929097 IC50 is effective to inhibit the gamma secretase functions. This inhibitor hinders the activation of the GS and checks the stimulation of Notch receptors which leads to tumor suppression.However RO4929097 does not have the ability to diminish the whole tumor cells or inhibit the cellular proliferation rather it generates slower and less transformed phenotype in cancer cells. RO4929097 price is very high and anyone can buy RO4929097 5 mg vial for around $300 form RO4929097 supplier. TheRO4929097 solubility is not clearly understood yet. It can be stored for 2 years at -20℃ for RO4929097 stability.

IN VIVO AND IN VITRO EXPERIMENTS OF RO4929097:

RPLC or reversed-phase liquid chromatography along with MS or mass spectroscopy was used to analyze the total as well as unbound RO4929097 present in human serum. This was done with success and the findings were very helpful for the pharmacokinetics studies of cancer patients [1].   

An abnormal Notch signaling is mostly reported in case of melanoma tumorigenesis or tumor progression, when in vivo and in vitro xenograft systems were exposed to RO4929097 the carcinogenic properties of cancer cell lines as well as the stem cells found to be inhibited. It is was noted that the HES1 protein levels were decreased which are regulated by the Notch and tumor cells were at low proliferation rates and soft colonies on agar of these cells are reported. The invasive property and size of tumor was also seen as reduced in case of xenografts [2]. Another group has reported almost similar effects in the leukemia of T -cell acute lymphoblasts [3]. A daily or intervals based dose of RO4929097 was proved to reduce the Hes1 and angiogenic genetic expression in number of xenografts models [4]. However in case of IL-6 and IL-8 the effects of this compound is limited and profiling of patients is needed in order to analyze the levels of IL-6 and IL-8 for proper RO4929097 based therapy [5].                  

RO4929097: CLINICAL SUCCESS

In patients having melanoma, neuroendocrine, sarcoma and ovarian cancer, RO4929097 has proved to be effective as it having good tolerance promoting long and stable effects of disease as the levels of IL-6/IL-8 are now pretests for this inhibitors therapy and I and II phase of  RO4929097 clinical trial was the confirmation for this [6]. RO4929097 has gained a remarkable success in the pediatric malignancies in vivo xenografts and solid tumors gave positive results for this compounda and it has also shown good results in case of  lymphoblastic leukemia (ALL and osteosarcoma xenografts [7].

NCI (National Cancer Institute) is reported about RO4929097 tolerance and side effects in patients having metastatic epithelial ovarian cancer or platinum resistant recurrent or follapian tubes cancer (NCT01175343). The multiple myeloma effects of this compouond are also analyzed in the phase II trials (NCT01251172). Some of the other studies are also performed having following referenced numbers solid malignant tumors (NCT01096355). Roche also reported its efficacy on non.small cell lung cancer 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 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. (24) (7)

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