Introduction: Gamma secretase Inhibition

Gamma secretase is an internal protease enzyme that is a complex of a number of subunits. Its mode of action is to cleave proteins that lie within the membrane-spanning domain, these include the amyloid precursor protein (APP) and the Notch. The Notch signaling pathway processes four different Notch receptors (1, 2, 3 and 4) which span the cell membrane. Upon extracellular interaction with a substrate protein the internal domain is released. This section of the protein then induced a signaling cascade within the cell nucleus to alter gene expression.[1] The function of the various NOTCH proteins is varied but in terms of cancer notch receptors have been demonstrated to be down regulated in basal cells carcinomas and cervical cancers. Notch 1 over-expression is associated with acute T cell leukemia and breast cancer  [2-4], Notch 3 receptor is over-expressed in 20% of ovarian cancers [5-7] while overexpression of Notch 4 is evident in murine models of breast cancer [8]. The field of research into NOTCH signaling is vast and beyond the scope of this document, simple put there existed evidence that inhibition of aberrant NOTCH over-expression would be an ideal target for chemotherapeutic activity. The development of inhibitors which would affect the action of NOTCH led to the targeting of the Gamma secretase enzyme. Developed by Roche the RO4929097 gamma secretase inhibitor represents a potent novel small molecule that is orally bioavailable.

RO4929097 Chemical Structure

RO4929097: Properties and Availability

RO4929097 structure is described as 2,2-dimethyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b, d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide and is available in high purity from a limited number of RO4929097 suppliers. RO4929097 price varies greatly between suppliers ranging from $150 – 400 for a 1 mg vial, to buy RO4929097 researchers are advised to shop carefully to obtain the best value for money. For RO4929097 stability in solution it is recommended that all stocks be stored at -20°C and freeze/thaw cycles is kept to a minimum. RO4929097 solubility is listed only for DMSO for concentrations of 10 mM, no indications are made for limit of solubility in terms of concentration or solvent.

RO4929097: Preclinical investigations

The IC50 for RO4929097 has been determined in both cell free and cellular assays as being in the low nM range[9]. Preclinically Ro4929097 has been tested on a panel of melanoma cell lines using xenograft models.  In vitro Ro4929097 demonstrated reduced proliferation impaired growth for primary melanoma cell lines. This was reflected in murine models where a decreased tumor volume and reduced invasion growth patterns was observed. [10] Conversely it has been report that in IL6 and IL8 over-expressing tumors RO4929097 is ineffective, indicating preselection of patient should be implemented in clinical trials. A patient group exhibiting low expression of IL6 and IL8 demonstrated a clear clinical benefit from RO4929097 [11]. In xenografts exposed to a daily or an intermittent schedule tumor reduction was observed with no associated toxicities, critically activity was continued even after treatment cessation [9]. As a part of the Pediatric Preclinical Testing Program (PPTP) RO4929097 was tested against a panel of 26 solid tumor xenografts. Significant anti-tumor activity was observed in 6 xenografts most notably in the Osteosarcoma panel. These results indicated the need for clinical phase I/II trial for this potent, novel treatment.

RO4929097: Clinical status

Limited or no data is available from completed clinical trials for RO4929097, although groups of patients have been treated in limited numbers suffering from, sarcoma, melanoma, ovarian and neuroendocrine tumors. Current clinical trials are being conducted with RO4929097 include an open-label study of RO4929097 in metastatic colorectal cancer (NCT01116687, phase II),: a phase I dose escalation trial of an exemestane / RO4929097 combination in metastatic breast cancer (ER+) (NCI 8539), Exemestane alone and in combination with RO4929097 in metastatic breast cancer (ER+) – phase 2, RO4929097 / Bevacizumab combination in recurrent malignant glioma (phase 1/2 - ABTC-1002), GDC-0449 / RO4929097 combination in advanced or metastatic sarcoma, Results from these trials are expected in 2013 and 2014.


   1.   Oswald F, Tauber B et al. p300 acts as a transcriptional coactivator for mammalian Notch-1. Mol Cell Biol 2001; 21(22):7761-7774.

   2.   Grabher C, von BH et al. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer 2006; 6(5):347-359.

   3.   Bertrand FE, Eckfeldt CE et al. Notch-1 and Notch-2 exhibit unique patterns of expression in human B-lineage cells. Leukemia 2000; 14(12):2095-2102.

   4.   Ma D, Dong X et al. Aberrant expression and clinical correlation of Notch signaling molecules in breast cancer of Chinese population. Asia Pac J Clin Oncol 2011; 7(4):385-391.

   5.   Park JT, Li M et al. Notch3 gene amplification in ovarian cancer. Cancer Res 2006; 66(12):6312-6318.

   6.   Park JT, Chen X et al. Notch3 overexpression is related to the recurrence of ovarian cancer and confers resistance to carboplatin. Am J Pathol 2010; 177(3):1087-1094.

   7.   Rose SL, Kunnimalaiyaan M et al. Notch 1 signaling is active in ovarian cancer. Gynecol Oncol 2010; 117(1):130-133.

   8.   Speiser J, Foreman K et al. Notch-1 and Notch-4 Biomarker Expression in Triple-Negative Breast Cancer. Int J Surg Pathol 2011.

   9.   Luistro L, He W et al. Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res 2009; 69(19):7672-7680.

10.   Huynh C, Poliseno L et al. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. PLoS One 2011; 6(9):e25264.

11.   He W, Luistro L et al. High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the gamma-secretase inhibitor, RO4929097. Mol Oncol 2011; 5(3):292-301.

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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. (95) (7)

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