Discovery and Optimization of Highly Selective Inhibitors of CDK5.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic human disease, but to date, only one therapy (tolvaptan) is approved to treat kidney cysts in ADPKD patients. Cyclin-dependent kinase 5 (CDK5), an atypical member of the cyclin-dependent kinase family, has been implicated as a target for treating ADPKD. However, no compounds have been disclosed to date that selectively inhibit CDK5 while sparing the broader CDK family members.

Discovery of a Potent and Selective TRPC5 Inhibitor, Efficacious in a Focal Segmental Glomerulosclerosis Model.

The nonselective Ca-permeable transient receptor potential (TRP) channels play important roles in diverse cellular processes, including actin remodeling and cell migration. TRP channel subfamily C, member 5 (TRPC5) helps regulate a tight balance of cytoskeletal dynamics in podocytes and is suggested to be involved in the pathogenesis of proteinuric kidney diseases, such as focal segmental glomerulosclerosis (FSGS). As such, protection of podocytes by inhibition of TRPC5 mediated Ca signaling may provide a novel therapeutic approach for the treatment of proteinuric kidney diseases.

Engineered production of iso-migrastatin in heterologous Streptomyces hosts.

Glutarimide-containing polyketides such as migrastatin (MGS) are well known for their ability to inhibit tumor cell migration. We have previously shown that MGS is derived from iso-migrastatin (iso-MGS) via a H(2)O-mediated ring-expansion rearrangement. A bacterial artificial chromosome (BAC) library of Streptomyces platensis NRRL18993, an iso-MGS producer, was constructed.