Development of New Tuberculosis Drugs: Translation to Regimen Composition for Drug-Sensitive and Multidrug-Resistant Tuberculosis

Tuberculosis (TB) kills more people than any other infectious disease. Challenges for developing better treatments include the complex pathology due to within-host immune dynamics, interpatient variability in disease severity and drug pharmacokinetics-pharmacodynamics (PK-PD), and the growing emergence of resistance. Model-informed drug development using quantitative and translational pharmacology has become increasingly recognized as a method capable of drug prioritization and regimen optimization to efficiently progress compounds through TB drug development phases. In this review, we examine translational models and tools, including plasma PK scaling, site-of-disease lesion PK, host-immune and bacteria interplay, combination PK-PD models of multidrug regimens, resistance formation, and integration of data across nonclinical and clinical phases.We propose a workflow that integrates these tools with computational platforms to identify drug combinations that have the potential to accelerate sterilization, reduce relapse rates, and limit the emergence of resistance.

Target Validation Using PROTACs: Applying the Four Pillars Framework

Proteolysis targeting chimeras (PROTACs) are heterobifunctional compounds that recruit the E3 ubiquitin ligase machinery to proteins of interest, resulting in their ubiquitination and subsequent proteasomal degradation. Targeted protein degradation has generated considerable interest in drug discovery because inhibition of one particular function of a protein often does not deliver the therapeutic efficacy that results from whole-protein depletion. However, the physicochemistry and intrinsically complex pharmacology of PROTACs present challenges, particularly for the development of orally bioavailable drugs. Here we describe the application of a translational pharmacology framework (called the four pillars) to expedite PROTAC development by informing pharmacokinetic–pharmacodynamic (PKPD) understanding and helping elucidate structure–activity relationships. Experimental methods are reviewed that help illuminate exposure of the drug or probe at the site of action (pillar 1) and engagement of its target(s) (pillar 2) that drive functional pharmacological effects (pillar 3) resulting in modulation of a relevant phenotype (pillar 4). We hope the guidance will be useful to those developing targeted protein degraders and help establish PROTAC molecules as robust target validation chemical probes.

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.