Sunday, March 25, 2012
JNJ-26481585 – AN ANTI-MYELOMA AGENT
The inhibitors to HDACs, target various HDAC enzymes and some of them are highly efficient against solid tumors. Some inhibitors need to be administered for a prolonged period of time. JNJ-26481585 is one such inhibitor which belongs to the group of 2nd generation of inhibitors. Under in vivo conditions it shows pharmacodynamic response for a prolonged period of time.
DISCOVERY OF THE SECOND GENERATION INHIBITOR JNJ-26481585
The inhibitors to HDACs generally show a potent action against HDACs belonging to class I, IIa and IIb. The HDAC enzymes belonging to class II are not generally involved in the survival of the solid cancers. Hence inhibition of this set of enzymes does not generally effect the growth and proliferation of tumor. The inhibitors to HDAC6 (belonging to the class IIb HDAC) decrease the movement of the cells. It also acts on ongogenic proteins like Hsp90 and depletes their levels. Inhibitors like paclitaxel and bortezomib show same effect. However the effects of these inhibitors were limited. Then the search began for some substances which can show potent anti-tumor activity and can efficiently inhibit the HDACs belonging to class I. After analyzing 140 lead compounds which were derived from pyrimidyl-hydroxamate, JNJ-26481585 was identified. In case of colon cancer cells it stimulated the hyperacetylation of histone H3. This further inhibited the tumor growth completely. It is presently undergoing clinical trials to prove its efficacy against various tumors .
ANTI-MYELOMA ACTIVITY OF JNJ-26481585
The pan-HDAC inhibitor JNJ-26481585 was tested in case of multiple myeloma cell lines (both primary and established in nature). It promoted the acetylation of the histones and increased the levels of those proteins which are members of Bcl2 family and promote apoptosis. It arrests the induction of Hsp72 and growth pathway. At a very low concentration it depletes the levels of Mcl-1 protein and stimulates the death of the myeloma cells .
JNJ-26481585 IS EFFECTIVE IN COMBINATION WITH OTHER INHIBITORS
Multiple myeloma is a malignancy within B-cells and is usually associated with severe bone disease and other complications. It leads to bone lesions which are lytic in nature and the skeletal events are disturbed. Biphosphonates are generally used for supportive care but they do not show any specific action towards bone lesions. Bortezomib was administered along with JNJ-26481585 on 5T2MM model. The combined effect of these inhibitors was a reduction in the number of osteoclasts along with an increase in the number of osteoblasts. The number and the bone volume of the trabecular bone were found to be increased. Angiogenesis is controlled and the tumor burden is reduced. The bone remodeling properties of Bortezomib were further enhanced by JNJ-26481585 hence making this combination highly efficient against multiple myeloma . The microenvironment of the bone marrow generally offers drug resistance and hence makes multiple myeloma incurable. JNJ-26481585 upregulates p21 and activates the caspase cascade. This affects the cell cycle by arresting it and stimulates the process of apoptosis within myeloma cells. It was selective in its action and showed no adverse effects within endothelial cells. It was potent at low concentrations.
JNJ-26481585 is effective in controlling the growth of myeloma and it enhances the efficiency of other inhibitors.
1. Arts J, King P, et al. JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity. Clin Cancer Res 2009 Nov 15; 15(22):6841-51.
2. Stühmer T, Arts J, et al. Preclinical anti-myeloma activity of the novel HDAC-inhibitor JNJ-26481585. British Journal of Haematology 2010 May; 149(4): 529–536.
3. Deleu S, Lemaire M, et al. Bortezomib Alone or in Combination with the Histone Deacetylase Inhibitor JNJ-26481585: Effect on Myeloma Bone Disease in the 5T2MM Murine Model of Myeloma. Cancer Res 2009 July 1; 69(5307).
4. Deleu S, Lemaire M, et al. The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine modelsThe effect of JNJ-26481585 in murine myeloma models. Leukemia 2009 Oct; 23(10):1894-903.