Publication Details (including relevant citation information):
Division of Medicinal Chemistry
General Poster Session
7:00 PM-9:00 PM, Sunday, 26 March 2006 Georgia World Congress Center -- Ex. Hall B4, Poster
The 231st ACS National Meeting, Atlanta, GA, March 26-30, 2006
Inhibitors of all-trans-retinoic acid (ATRA) metabolism enzymes (CYP26s), also called retinoic acid metabolism blocking agents (RAMBAs) are proving to be useful anticancer agents. In the search for new RAMBAs, we utilized IC50 values of known RAMBAs to generate a common feature-based pharmacophore model using the Catalyst HipHop approach. A total of ten Hypotheses were generated with high ranking scores (86.8 - 90.6). Hypothesis-2 and Hypothesis-3 were selected on the bases of GH analysis and knowledge of the ligandenzyme interaction. These two hypos were used to retrieve potential new RAMBAs from the NCI and Maybridge databases. Two of the compounds retrieved using Hypo-3 (NCI0308597 and HST01914) were, tested for biological activity at 100 nM. These compounds showed 54.7% and 53.2 % inhibition of ATRA metabolism respectively. The activity results indicate that Hypo-3 with five hydrophobic and two hydrogen bond acceptor features is a good representative hypothesis for identifying new RAMBAs.
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