Purushottamachar Puranik - Retinoic acid metabolism blocking agents: Chemical feature based pharmacophore

Version 1

      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.

      Address (URL): http://