steroid hormone action by way of multiple kinase pathways initiated by cell surface growth factor receptors. Under the guidance of a multitude of protein remodelers to form a multiprotein coactivator complex that can interact with the phosphorylated ER at a specific gene promoter site, the core coactivator first has to recruit a specific set of cocoactivators. The proteins that the core coactivator assembles as the core coactivated complex have individual enzymatic activities to methylate or acetylate adjacent proteins. The ER substrates or coenzyme A can be polyubiquitinated by multiple cycles of the reaction or, depending on linkage proteins, they can either be activated further or degraded by the 26S proteasome. Consequently, to have an effective gene transcription that is programmed and targeted by the structure and phosphorylation status of the ER and coactivators, it is required to have a dynamic and cyclic process of remodeling capacity for transcriptional assembly, after which the transcription complex is then instantly routinely destroyed by the proteasome. Structure and function Structure–activity relationships The core structure of SERMs simulates the 17β-estradiol template. They have two aromatic rings separated by 1-3 atoms (often a stilbene-type of arrangement). Between the two phenyls of the core, SERMs typically have a 4-substituted phenyl group that, when bound to ER, projects from a position of an estratriene nucleus so that helix 12 moves from the receptor opening and blocks the space where coactivator proteins would normally bind and cause ER agonist activity. There has been a lot of variations in the core portion of SERMs while there has been less flexibility with what is tolerated in the side chain. SERMs can be classified by their core structure. First-generation triphenylethylenes The first main structural class of SERM-type molecules reported are the triphenylethylenes. The stilbene core (similar to the nonsteroidal estrogen, diethylstilbestrol) essentially mimics steroidal estrogens such as 17β-estradiol, while the side chain overlays with the 11th position of the steroid nucleus. Triphenylethylene derivatives have an additional phenyl group attached to the ethylene bridge group. The 3-position H-bonding ability of phenols is a significant requirement for ER binding. The first drug, clomifene, has a chloro-substituent on the ethylene side chain which produces similar binding affinities as the later discovered drug tamoxifen. Clomifene is a mixture of estrogenic (cis-form) and antiestrogenic isomers (trans-form). Cis and trans are defined in terms of the geometric relationships of the two unsubstituted phenyl rings. The two isomers of