Artificial transcriptional activators are excellent tools for studying the mechanistic details of transcriptional regulation. Furthermore, as the correlation between a wide range of human diseases and misregulated transcription becomes increasingly evident, such molecules may in the long run serve as the basis for transcription-based therapeutic agents. The greatest challenge in this arena has been the discovery of organic molecules that are functional mimics of transcriptional activation domains, sequences of natural proteins that participate in a variety of protein-protein interactions to control transcriptional levels. We describe the first examples of small molecules that function in this capacity, isoxazolidines containing an array of polar and hydrophobic functional groups. Despite their small size, the most potent of the structures functions nearly as well as a natural activation domain.

Small molecules that reconstitute the binding mode(s) of a protein and in doing so elicit a programmed functional response offer considerable advantages in the control of complex biological processes. The development challenges of such molecules are significant, however. Many protein-protein interactions require multiple points of contact over relatively large surface areas. More significantly, several binding modes can be superimposed upon a single sequence within a protein, and a true small molecule replacement must be pre-programmed for such multi-modal binding. This is the case for the transcriptional activation domain or TAD of transcriptional activators as these mofifs utilize a poorly characterized multi-partner binding profile in order to stimulate gene expression. Here we describe a unique class of small molecules that exhibit both function and a binding profile analogous to natural transcriptional activation domains. Of particular note, the small molecules are the first reported to bind to the KIX domain within the CREB binding protein (CBP) at a site that is utilized by natural activators. Further, a comparison of functional and non-functional small molecules indicates that an interaction with CBP is a key contributor to transcriptional activity. Taken together, the evidence suggests that the small molecule TADs mimic both the function and mechanism of their natural counterparts and thus present a framework for the broader development of small molecule transcriptional switches.Transcriptional activators are essential for high fidelity transcription, responsible for seeking out particular genes and up-regulating them to precise levels in a signal-responsive fashion.(1,2) Indeed, the altered transcription patterns observed in disease states can often be attributed to malfunctioning and/or mis-regulated transcriptional activators.(3-6) Alterations in the function of the tumor suppressor p53, for example, are found in >50% of all human cancers; (7,8) similarly, constitutively active NF-κB, an activator that regulates genes responsible for apoptosis, inflammatory response, and proliferation, is observed in inflammatory disorders and most cancers.(9,10) There is thus tremendous interest in the development of activator artificial transcription factors (activator ATFs), nonnatural molecules programmed to perform the same function as endogenous activators, as both mechanistic tools and as transcription-targeted therapeutic agents. (2,(11)(12)(13)(14) The architecture of activator ATFs is analogous to that of their natural counterparts in that they minimally consist of a DNA binding domain (DBD) that confers gene-targeting specificity and a transcriptional activation domain (TAD) that controls *Corresponding author, amapp@umich.edu.. The challenges associated with small molecule TAD discovery are due in large part to the scarcity of molecular-level details regarding natural TAD function. The largest and most well studied class of activators is the amphipathic class, characterized by interspersed polar a...

Summary: A mathematical model of the acid catalyzed 1,3‐propanediol polymerization has been developed. Two catalysts investigated include sulfuric acid and superacid (tetrafluoroethane sulfonic acid or triflic acid). Based on a detailed reaction mechanism, population and mass balance equations have been derived for small molecules as well as for polymeric species of numerous chain distributions, which are distinguishable in terms of protonation state and end group functionality. Due to the interaction of the sulfuric acid catalyst with the polymer ends, a novel, dual index polymer chain distribution was derived and implemented.The model has been validated with various sets of experimental data obtained in a lab‐scale reactor setup. Dynamic model outputs such as monomer concentration, molecular weight averages, unsaturated and sulfate end groups, water evaporation rate and sulfate middle groups have been compared with experimental data of sulfuric and super acid catalyzed polymerization runs. Very good agreement between model predictions and experimental data has been obtained for both catalyst systems over an extended range of conditions using the same set of model parameter values. It is worth noting that the model is also capable of predicting polymerization equilibrium.

The link between a growing number of human diseases and misregulation of gene expression has spurred intense interest in artificial transcriptional activators that could be used to restore controlled expression of affected genes. To expand the repertoire of activation domains available for the construction of artificial transcriptional regulators, a selection strategy was used to identify two unique activation domain motifs. These activation domains bear little sequence homology to endogenous counterparts and bind to unique sites within the transcriptional machinery. A comparison with two well-characterized activation domains, VP2 and P201, demonstrated for the first time that functional potency is not solely dictated by binding affinity. Finally, the selection strategy described is readily applicable to the identification of small molecule activation domains.