JNTX-101, a novel albumin-encapsulated gemcitabine prodrug, is efficacious and operates via caveolin-1-mediated endocytosis.

Albumin is an attractive candidate carrier for the development of novel therapeutic drugs. Gemcitabine has been FDA approved for the treatment of solid tumors; however, new drugs that optimize gemcitabine delivery are not available for clinical use. The aim of this study was to test the efficacy of a novel albumin-encapsulated gemcitabine prodrug, JNTX-101, and investigate whether Cav-1 expression predicts the therapeutic efficacy of JNTX-101. We first determined the treatment efficacy of JNTX-101 in a panel of pancreatic/lung cancer cell lines and found that increases in Cav-1 expression resulted in higher uptake of albumin, while Cav-1 depletion attenuated the sensitivity of cells to JNTX-101. In addition, decreased Cav-1 expression markedly reduced JNTX-101-induced apoptotic cell death in a panel of cells, particularly in low-serum conditions. Furthermore, we tested the therapeutic efficacy of JNTX-101 in xenograft models and the role of Cav-1 in JNTX-101 sensitivity using a Tet-on-inducible tumor model in vivo. Our data suggest that JNTX-101 effectively inhibits cell viability and tumor growth, and that Cav-1 expression dictates optimal sensitivity to JNTX-101. These data indicate that Cav-1 correlates with JNTX-101 sensitivity, especially under nutrient-deprived conditions, and supports a role for Cav-1 as a predictive biomarker for albumin-encapsulated therapeutics such as JNTX-101.

Crystal structures of PRK1 in complex with the clinical compounds lestaurtinib and tofacitinib reveal ligand induced conformational changes.

Protein kinase C related kinase 1 (PRK1) is a component of Rho-GTPase, androgen receptor, histone demethylase and histone deacetylase signaling pathways implicated in prostate and ovarian cancer. Herein we describe the crystal structure of PRK1 in apo form, and also in complex with a panel of literature inhibitors including the clinical candidates lestaurtinib and tofacitinib, as well as the staurosporine analog Ro-31-8220. PRK1 is a member of the AGC-kinase class, and as such exhibits the characteristic regulatory sequence at the C-terminus of the catalytic domain--the 'C-tail'. The C-tail fully encircles the catalytic domain placing a phenylalanine in the ATP-binding site. Our inhibitor structures include examples of molecules which both interact with, and displace the C-tail from the active site. This information may assist in the design of inhibitors targeting both PRK and other members of the AGC kinase family.