Many drug candidates fail in clinical trials due to insufficient therapeutic window. We posit that improvements in therapeutic window can be accomplished using kinetic selectivity. In particular, drugs that have sustained target occupancy may have extended activity at low drug concentration enabling dosing frequency and exposure to be reduced. The goal of the Center is to identify the molecular factors that control the translation of sustained occupancy to extended efficacy. Activities include the identification, design and synthesis of compounds with altered binding kinetic profiles, the interrogation of time-dependent drug activity at the cellular level and in preclinical models of disease, and the development of mechanistic PK/PD models that enable the kinetic parameters for time-dependent enzyme inhibition to be used to predict in vivo drug efficacy. These approaches will be used to create target vulnerability functions and identify targets that will benefit from kinetic selectivity. Translational activities include the development of positron emission tomography (PET) radiotracers to non-invasively interrogate target engagement in humans.
Stony Brook University has made a major investment in the infrastructure to support PET imaging including the installation of a cyclotron for radioisotope production, facilities for cGMP radiotracer synthesis, preclinical and clinical imaging systems including a human PET/MR scanner, and the recruitment of faculty with expertise in all aspects of PET imaging.
Kinetic selectivity is relevant in all diseases and currently the Center is studying targets in oncology, inflammation and infection. The Center is also establishing collaborations to expand into additional target space.
Review: Tonge (2018) Drug–Target Kinetics in Drug Discovery. ACS Chem Neurosci 9, 29-39. http://pubs.acs.org/doi/pdf/10.1021/acschemneuro.7b00185