Design of BET Inhibitor Bottlebrush Prodrugs with Superior Efficacy and Devoid of Systemic Toxicities.

Prodrugs engineered for preferential activation in diseased versus normal tissues offer immense potential to improve the therapeutic indexes (TIs) of preclinical and clinical-stage active pharmaceutical ingredients that either cannot be developed otherwise or whose efficacy or tolerability it is highly desirable to improve. Such approaches, however, often suffer from trial-and-error design, precluding predictive synthesis and optimization. Here, using bromodomain and extra-terminal (BET) protein inhibitors (BETi)-a class of epigenetic regulators with proven anticancer potential but clinical development hindered in large part by narrow TIs-we introduce a macromolecular prodrug platform that overcomes these challenges. Through tuning of traceless linkers appended to a "bottlebrush prodrug" scaffold, we demonstrate correlation of in vitro prodrug activation kinetics with in vivo tumor pharmacokinetics, enabling the predictive design of novel BETi prodrugs with enhanced antitumor efficacies and devoid of dose-limiting toxicities in a syngeneic triple-negative breast cancer murine model. This work may have immediate clinical implications, introducing a platform for predictive prodrug design and potentially overcoming hurdles in drug development.

Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs.

At present there are no drugs for the treatment of chronic liver fibrosis that have been approved by the Food and Drug administration of the United States. Telmisartan, a small-molecule antihypertensive drug, displays antifibrotic activity, but its clinical use is limited because it causes systemic hypotension. Here, we report the scalable and convergent synthesis of macromolecular telmisartan prodrugs optimized for preferential release in diseased liver tissue. We optimized the release of active telmisartan in fibrotic liver to be depot-like (that is, a constant therapeutic concentration) through the molecular design of telmisartan brush-arm star polymers, and show that these lead to improved efficacy and to the avoidance of dose-limiting hypotension in both metabolically and chemically induced mouse models of hepatic fibrosis, as determined by histopathology, enzyme levels in the liver, intact-tissue protein markers, hepatocyte necrosis protection, and gene-expression analyses. In rats and dogs, the prodrugs are retained long-term in liver tissue and have a well-tolerated safety profile. Our findings support the further development of telmisartan prodrugs that enable infrequent dosing in the treatment of liver fibrosis.

Publisher Correction: Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs.

In the version of this Article originally published, the author Peter Blume-Jensen was not denoted as a corresponding author; this has now been amended and the author's email address has been added. The 'Correspondence and requests for materials' statement was similarly affected and has now been updated with the author's initials 'P.B-J.'

Phosphorylation of Minor Lipids of Human Milk Tightly Bound to Secretory Immunoglobulin A.

Catalytic antibodies or abzymes possessing the different catalytic activities were detected in the sera of patients with various autoimmune pathologies, where their presence is most probably associated with autoimmunization. Normal humans are generally considered to have no abzymes, since no obvious immunizing factors are present. The ability of small fraction of sIgA from human milk to phosphorylate selectively casein in the presence of gamma(32)P-ATP was previously shown to be a property of the Abs. Here we revealed for the first time that the same small fraction of sIgA contains Ab subfraction, which is tightly bound to unusual minor lipids of human milk. The lipids may be phosphorylated in the presence of gamma(32)P-ATP and remain partially bound to Abs after purification of polyclonal sIgA by several sequential chromatographies. These lipids may be effectively separated from sIgA only by gel filtration in a buffer containing 5% dioxane or by extraction of the sIgA solutions with chloroform-methanol mixture. It has been shown that two minor milk phospholipids, similarly to the previously described GM1, GM3 and GD3 gangliosides contain residue of sialic acid, but in conrast to the latter lipids, they can not be oxidized with sodium periodate; alkaline methanolysis of them results in formation of 4 and 5 products respectively, while hydrolysis of the gangliosides gives only one or two products. All the data obtained give an evidence in favor of that the minor lipids tightly bound to sIgA may be considered as new lipids of human milk. It was suggested that phosphorylation of the lipids is catalyzed by sIgA antibodies.