Discovery of Osivelotor (GBT021601): A Potent, Next-Generation Sickle Hemoglobin Polymerization Inhibitor.

This report details the discovery path of GBT021601 (osivelotor) (), a novel, small molecule, sickle hemoglobin (HbS) polymerization inhibitor. Following a streamlined testing funnel with cassette dosing in rat pharmacokinetic (PK) studies, we identified this next-generation HbS polymerization inhibitor, which had improved PK properties compared with the first-in-class drug, voxelotor (). GBT021601 has ∼4.

Mechanistic intracellular PK/PD modeling to inform development strategies for small interfering RNA therapeutics.

Small interfering RNA (siRNA) therapeutics provide a targeted approach to silence disease-related genes, with notable success in liver-targeting applications. However, the quantitative effects of siRNA properties, such as stability and affinity, as well as biological factors like cell proliferation, mRNA turnover, and abundance, on gene silencing, particularly for extrahepatic targets, remain poorly understood. To identify determinants influencing gene knockdown extent and duration, we developed a mechanistic intracellular pharmacokinetic/pharmacodynamic (PK/PD) model for RNAiMAX-delivered siRNA, based on cytoplasmic siRNA disposition, RISC-loaded siRNA exposure, and mRNA knockdown across different targets in MCF7 and BT474 cells.

Enhancing PDT efficacy in NMIBC: Efflux inhibitor mediated improvement of PpIX levels and efficacy of the combination of PpIX-PDT and SO-cleavable prodrugs.

Protoporphyrin IX (PpIX)-based photodynamic therapy (PDT) has shown limited efficacy in nonmuscle-invasive bladder cancer (NMIBC). To improve PDT efficacy, we developed singlet oxygen-cleavable prodrugs. These prodrugs, when combined with PpIX-PDT, induce cancer cell death through both PDT and drug release mechanisms.

A highly sensitive stem-loop RT-qPCR method to study siRNA intracellular pharmacokinetics and pharmacodynamics.

Small interfering RNA (siRNA) is a powerful tool for sequence-specific silencing of disease-related genes. In this study, we established and validated a stem-loop reverse transcription-quantitative polymerase chain reaction (RT-qPCR) method applicable for both chemically unmodified and modified siRNA, aiming to elucidate mechanistic intracellular pharmacokinetic and pharmacodynamic (PK/PD) properties of siRNA. We conducted a comprehensive evaluation of factors affecting intracellular siRNA quantification.