| Nuclear/steroid hormone receptors function as ligand-dependent transcriptional regulators of diverse sets of genes involved in development and homeostasis. Mutations to these receptors are associated with several diseases, including cancer. Two mutations to the peroxisome proliferator-activated receptor gamma (PPARgamma), V290M and P467L, have been identified in patients with early onset non-insulin dependent diabetes mellitus (NIDMM) and severe insulin resistance. These mutations are severely impaired in their response to endogenous PPAR ligands, as well as the synthetic agonist, rosiglitazone. The mutations are believed to prevent the receptor from adopting an active conformation. Molecular modeling was used to identify key points of modification to a known agonist, farglitazar, in an attempt to restore activity to the mutant receptor. It was believed that additional hydrophobic contacts would help stabilize the proper folding of helix-12, thereby restoring activity to the receptor.; Mutations to the androgen receptor (AR) have been linked to the failure of hormonal therapy in the treatment of prostate cancer (PCa). It has been proposed that AR mutations such as Thr877Ala, Trp741Leu, and Trp741Cys that cause anti-androgens such as flutamide and bicalutamide to function as agonists are likely associated with the anti-androgen withdrawal syndrome in PCa therapy. The recently solved crystal structure of bicalutamide in Trp741Leu was used to design analogs that would maintain antagonism in the Trp741Leu mutation. A series of ligands were synthesized that contained additional aryl moieties that were reasoned to prevent helix-12 from adopting an agonist conformation. Three analogs in particular, PLM1, PLM2 and PLM6, showed potent antagonistic activity in all three mutations as well as wild-type, suggesting that these analogs may be considered "pan-antagonists" of AR. Molecular modeling was found to be a useful guide that provides insight into which ligands may have a greater propensity to be antagonists. This was the first example of a designed compound targeting a mutation that causes resistance to antagonists. |
