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Givinostat is a derivative of hydroxamic acid and is within the early phases of clinical development. Large scale research has shown that the primary causes behind cancer are genetic mutations and epigenetic modifications. It is very difficult to correct the gene mutations whereas epigenetic modifications can be reversed. Histone decetylases play a vital role in stimulating epigenetic changes hence recent focus is on the development of inhibitors to HDACs which can correct conditions like cancers, neurological disorders etc. The acetylation levels of chromatin are altered by these inhibitors. They also modulate the acetylation levels of certain non histone proteins ultimately leading to alternations in gene expressions. Certain vital functions of the cell like division, and apoptosis are also modulated by these inhibitors. Within human beings at least 18 HDAC enzymes have been traced. HISTORY OF DEVELOPMENT OF GIVINOSTAT The derivatives of hydroxamic acids have been well studied as inhibitors. Vorinostat also belongs to the same group of hydroxamic acid derived compounds and has been approved by FDA for clinical administration. Few other hydroxamates which are presently undergoing clinical trials include Givinostat, R306465, JNJ-16241199 and PCI 24781. These inhibitors inhibit the activity of enzymes at low concentrations. Multiple myeloma patients (either progressive or relapsed) underwent through phase II clinical testing with Givinostat. A 100 mg of Givinostat, given twice daily was tolerated to the maximum level by the patients. After the analysis of the side effects and the tolerance levels, scientist came to a conclusion that, Givinostat is moderately tolerated. Few inhibitors derived from cinnamic acid like Belinostat and Panobinostat have become clinically more important due to their specificity in action [1]. A PILOT STUDY OF GIVINOSTAT A mutation within JAK2 enzyme (Valine to phenylalanine substitution at 617th position) is commonly seen in case of Myelofibrosis, Polycythaemia Vera and Thrombocythaemia. The efficiency of Givinostat as an inhibitor was analyzed under phase IIA. This inhibitor was administered twice daily (50 mg each time). However the treatment had to be discontinued due to the progression of disease. The disappearance of Pruritus, was noticed in case of Myelofibrosis patients. Splenomegaly was found to be reduced in case of 75% of patients, suffering from Polycythaemia Vera. An over all reduction in the allelic burden of JAK2V617F was noticed. These results also project that haematological response is stimulated in patients suffering from Polycythaemia Vera and Myelofibrosis [2]. JAK2V617F is the primary cause of myeloproliferative neoplasm. Inhibitors to JAK2 like Pan-JAK had been synthesized within a short duration of 5 years. These inhibitors have been tested under in vitro and in vivo conditions. However these inhibitors failed to perform like imatinib (acts against myeloid leukemia). The capacity of these inhibitors to reduce the allele burden (JAK2V617F mutation) has been found to be very weak. Hence the future research targets to discover a combination therapy including JAK2 inhibitors to overcome myeloproliferative neoplasm [3]. CLINICAL ACTIVITY OF GIVINOSTAT ASSESSED IN CASE OF HODGKIN LYMPHOMA Givinostat has been tested in MM and Hodgkin lymphoma under phase II clinical trials. This inhibitor shows only moderate benefits. A combination therapy using Givinostat and meclorethamine was tested under phase II clinical trials to analyze its efficacy against Hodgkin lymphoma. This combination was tested in both the cases of refractory or relapsed lymphoma. This combination was found to be safe for administration. TARC levels were found to be reduced during the early stages and this served as a biomarker. This biomarker helped to study the reaction to the therapy [4]. CONCLUSION In summary, Givinostat is potent inhibitor of HDACs which controls the growth of cancer both alone and in combination with other inhibitors. As one of the world leading suppliers of high-performance life-science products. We have over 8,000 products which consist of inhibitors, antibodies, RNAis, proteins and peptides those which focus on signaling pathways such as Cabozantinib, Navitoclax, NVP-BEZ235 & so on. Furthermore, compound libraries for high-throughput screening and high-content screening are also available.
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GIVINOSTAT, Vorinostat, Belinostat,
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