663180-96-9Relevant academic research and scientific papers
Pyrazole-based potent inhibitors of GGT1: Synthesis, biological evaluation, and molecular docking studies
Mansha, Muhammad,Kumari, Udayappan Udhaya,Cournia, Zoe,Ullah, Nisar
, p. 666 - 676 (2016/09/14)
In this study, a series of pyrazole-based structural analogues of GGTI-DU40 (1) have been synthesized and biologically evaluated for geranylgeranyltransferase 1 (GGT1) and farnesyltransferase (FT) inhibition. The screening results revealed that 2 (IC50?=?2.4?μM) and 5 (IC50?=?3.1?μM) are potent GGT1 inhibitors (GGTIs), possessing higher inhibitory activity compared to the control compound 1 (IC50?=?3.3?μM). The anti-proliferative efficacy of these compounds was further assayed against MDA-MB-231?cells which indicated a significantly higher activity of 2 (IC50?=?7.6?μM) compared to 1 (IC50?=?23.0?μM). To examine the capacity of the synthesized compounds to inhibit GGT1 in an intact cell, western blot analysis was performed on the MDA-MB-231?cell line, which revealed very high inhibitory cellular activity of 2 and 5 and demonstrated their capacity to inhibit prenylation of endogenous proteins. Molecular docking studies of 2 against the crystal structure of GGT1 complexed with a geranylgeranyl pyrophosphate (GGPP) Analog and a CaaX (C?=?cysteine, aa?=?aliphatic amino acids, and X?=?any amino acid) portion of the KKKSKTKCVIL peptide substrate revealed several hydrogen bonding interactions and π-π contacts between 2 and the binding pocket of GGT1. Together these data suggest that compound 2 could proceed to in?vivo investigation to further assess its efficacy and cytotoxicity.
Prenylation inhibitors and methods of their synthesis and use
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Page 85, (2008/06/13)
The present invention is directed to compounds useful in the treatment of diseases associated with prenylation of proteins and pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising same, and to methods for inhibiting protein prenylation in an organism using the same.
