Many cancers change their energy metabolic requirements and become "glutamine addicted" for their growth and survival. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) has shown robust efficacy in both preclinical animal models and exploratory clinical studies. Although promising, clinical studies with DON were halted due to its marked dose-limiting toxicities, which were mainly gastrointestinal (GI)-related, as the GI system is highly dependent on glutamine utilization. To overcome these toxicity issues, we sought to develop a DON prodrug that could selectively deliver DON to tumor tissues while sparing normal glutamine-dependent tissues like the GI tract. We designed over 100 prodrugs by installing dual promoeities on DON that can be dislodged by the enriched milieu of esterase and protease enzymes in tumor. Using iterative chemistry and pharmacokinetic efforts, we identified various promising DON prodrugs that showed preferential tumor bioactivation and delivery. Of these, our best DON prodrug, DRP-104 is bio-activated in the tumor while bio-inactivated in gastrointestinal (GI) tissues resulting in 11-fold higher glutamine antagonist delivery to the tumor (target site) versus GI (toxicity site) resulting in robust anti-cancer activity with minimal GI-toxicities. DRP-104, is now being evaluated in Ph1/2a clinical trials in cancer patients (ClinicalTrials.gov Identifier: NCT04471415).

References:
Leone et al., Science 366, 1013-1021 (2019)
Rais et al., Sci. Adv. 8, eabq5925 (2022)

In vitro drug transporter data are critical for understanding drug-drug interaction potential, but those data are only useful if conclusions can be drawn. Researchers are plagued with practical challenges associated with compounds that are unstable, sticky or insoluble, resulting in convoluted or inconclusive results. Three interesting transporter case studies are presented, each highlighting a creative solution to explore perplexing initial results and generate useful data, despite problematic physicochemical characteristics of the drugs involved.

This webinar is sponsored by BioIVT.

Target-mediated drug disposition (TMDD) is a term to describe a nonlinear pharmacokinetics (PK) phenomenon that is caused by high-affinity binding of a compound to its pharmacologic targets. As the interaction between drug and its pharmacologic target belongs to the process of pharmacodynamics (PD), TMDD can be viewed as a consequence of "PD affecting PK". Both large-molecule and small-molecule compounds can undergo TMDD. However, TMDD in large-molecule compounds is well known due to its high prevalence, while TMDD in small molecule compounds is more counter-intuitive and has been an overlooked area. Recognizing TMDD in small-molecule compounds is important, as the information can be leveraged to select the appropriate dose regimen, improve clinical trial design, as well as predict pharmacological target occupancy. This webinar summarizes the general pharmacokinetic features that facilitate the recognition of small-molecule TMDD, provides case examples of different classes of small-molecules exhibiting TMDD, highlights the importance of recognizing TMDD of small-molecule compounds during clinical development, and presenting the pharmacometric models that have been used to facilitate the quantitative understanding of small molecules exhibiting TMDD.

This webinar will highlight the challenges and limitations for prediction of in vivo clearance for aldehyde oxidase (AO) substrates in human. Further, the consequences of poor prediction of AO clearance when developing physiologically-based pharmacokinetic (PBPK) models for AO and dual AO-CYP substrates will be explained. Attendees will receive the latest research aimed at overcoming these challenges being performed by two academic centres of excellence.Joint webinar between Centre for Applied Pharmacokinetic Research (CAPKR; University of Manchester, UK) and Proteomics-based Research Initiative for Non-Cytochrome P450 Enzymes (PRINCE; Washington State University, US), two academic research consortia sponsored by pharmaceutical industry. Co-chairs: - Dr Daniel Scotcher (University of Manchester, UK) - Dr. Bhagwat Prasad (Washington State University, WA). 

Aldehyde oxidase (AO) is a cytosolic molybdoflavoprotein enzyme, expressed mainly in liver, with wide range of substrates and capable of mediating oxidation and reduction metabolism. Following from progress towards reducing cytochrome P450 (CYP) liabilities of new drugs, AO has emerged as an increasingly common alternative metabolic pathway for drug metabolism. In particular, several drug development programs have failed due to poor prediction of in vivo drug clearance by AO; for example, toxicity and poor bioavailability in first-in-human trials. This webinar will explain the existing challenges of in vitro-in vivo extrapolation (IVIVE) of intrinsic clearance of AO and dual AO CYP substrates from a variety of in vitro systems, and the latest research to resolve these. The development of physiologically-based pharmacokinetic (PBPK) models for AO and dual AO-CYP substrates will be presented. In particular, the value and challenges of proteomics abundance data across tissues and population groups, and reverse translation of clinical data will be discussed. Relevance to clinical pharmacology including drug-drug interactions and dose adjustment in specific populations will be discussed.

Speakers: 

- Dr Sandhya Subash (Washington State University, WA): "Key Factors Affecting Quality and Translatability of in vitro AO Mediated Metabolism Data"

- Dr Nihan Izat (University of Manchester, UK): "Current Perspectives on IVIVE of Aldehyde Oxidase and PBPK Modelling Strategies"

Unique GSH adduct formation was found in this study where the GSH adduct was formed through rearrangement reaction. So, there was no characteristic -129 neutral loss in this rearranged GSH adduct. Additionally it was direct GSH adduct where no CYP mediated Bioactivation was required. The GSH adduct formation was catalyzed by ?-glutamyltranspeptidase and non specific peptidase. The GSH adduct formation was compared between Pyrimidine, Pyridazine and Pyridine series and it was found that GSH adduct formation was maximum in case of Pyrimidine followed by Pyridazine and Pyridine. This trend was in keeping with the diminishing electrophilicity across these series, as demonstrated by in silico modeling. Hence, mechanistic insights gained from this study could be used to assist a medicinal chemistry campaign to design compounds that were less prone to the formation of reactive metabolites.

Certain aromatic nitriles are well-known inhibitors of cysteine proteases.The mode of action of these compounds involves the formation of a reversible or irreversible covalent bond between the nitrile and a thiol group in the active site of the enzyme. However, the reactivity of these aromatic nitrile-substituted heterocycles may lead inadvertently to nonspecific interactions with DNA, protein, glutathione, and other endogenous components, resulting in toxicity and complicating the use of these compounds as therapeutic agents. In the present study, the intrinsic reactivity and associated structure y property relationships of cathepsin K inhibitors featuring substituted pyridazines [6-phenylpyridazine-3-carbonitrile, 6-(4-fluorophenyl)-pyridazine-3-carbonitrile, 6-(4-methoxyphenyl)pyridazine-3-carbonitrile, 6-p tolylpyridazine-3-carbonitrile], pyrimidines [5-ptolylpyrimidine-2-carbonitrile, 5-(4-fluorophenyl)pyrimidine-2-carbonitrile], and pyridines [5-p-tolylpicolinonitrile and 5-(4-fluorophenyl)picolinonitrile] were evaluated using a combination of computational and analytical approaches to establish correlations between electrophilicity and levels of metabolites that were formed in glutathione- and N-acetylcysteine-supplemented human liver microsomes.

 Metabolites that were characterized in this study featured substituted thiazolines that were formed following rearrangements of transient glutathione and N-acetylcysteine conjugates. Peptidases including ?-glutamyltranspeptidase were shown to catalyze the formation of these products, which were formed to lesser extents in the presence of the selective ?-glutamyltranspeptidase inhibitor acivicin and the nonspecific peptidase inhibitors phenylmethylsulfonyl fluoride and aprotinin. Of the chemical series mentioned above, the pyrimidine series was the most susceptible to metabolism to thiazoline-containing products, followed, in order, by the pyridazine and pyridine series. This trend was in keeping with the diminishing electrophilicity across these series, as demonstrated by in silico modeling. Hence, mechanistic insights gained from this study could be used to assist a medicinal chemistry campaign to design cysteine protease inhibitors that were less prone to the formation of covalent adducts.

Attendees will be educated on the need to understand effect of disease state on transport activity and PK of drugs. Emerging modeling approach to predict PK in NASH/Hepatic impairment population will be discussed. Enable model-informed drug development - understanding disease effects.

The liver and kidney play central role in the pharmacokinetics (PK) of drugs and new molecular entities (NMEs). Several solute carriers (SLCs) including OATP1B1/1B3/2B1, NTCP, OAT2 and OCT1 and efflux pumps including MRPs, Pgp, BCRP are highly expressed on the sinusoidal/canalicular membranes and have the potential to dictate hepatic clearance. Similarly, renal transporters (OCT2/OATs/MATEs) are important in the renal elimination of drugs and metabolites. Disease-states such as renal- and hepatic-impairment is associated with multiple pathophysiological and biological changes including variable and non-uniform reduction in metabolic/transporter activity, altered plasma protein binding, hepatic blood flow and portal-systemic shunting, etc. and may lead to altered blood or plasma clearance of drugs eliminated by liver. This presentation will discuss the disease-induced changes in expression and function of OATP1B and other drug transporters along with drug metabolizing enzymes, and the implications on the clinical pharmacokinetics in patient populations. Emphasis will be placed on the proteomics- and/or PBPK-informed translation to predict PK changes in organ impairment.

This talk is meant to inform the global drug metabolism and pharmacokinetics research and applications community of DMPK work being done in Africa. It is hoped to highlight opportunities for research collaboration. This webinar intends to focus on the following objectives:

1. Present progress in DMPK research and applications in Africa;

2. To demonstrate how preclinical and clinical DMPK has improved the use of drugs in the treatment of infectious diseases;

3. To make the Global scientific community aware of the liver tissue biobank from people of African ancestry as a DMPK research resource they can access.

This webinar aims to introduce various tools/platforms, the use of primary human hepatocyte spheroids, cryo-electron microscopy, and bioengineered microRNA, in drug transporter research and drug discovery. The webinar also aims to recognize graduate students and postdoctoral fellows from academia who carried out transporter-related research and presented their work in the form of a poster at the 2022 ISSX/MDO International Meeting.

This webinar will feature three presentations and help scientists better understand:
1) the utility of using 3D primary human hepatocyte spheroids to study hepatic transporters
2) application of bioengineered microRNA in regulation of solute carrier (SLC) transporters
3) the structures of organic cation transporters revealed by electronic microscopy which help understand substrate or inhibitor binding with transporters.

This presentation provides an overview of mechanistic PK models developed to characterize ADME properties of therapeutic proteins (TPs), which can be used to support model-informed discovery and development of TPs. As the next-generation of TPs with diverse physicochemical properties and mechanism-of-action is being developed rapidly, there is an urgent need to better understand the determinants for the ADME of TPs and evolve existing platform PK models to facilitate successful bench-to-bedside translation of these promising drug molecules.

This webinar aims to highlight current knowledge about albumin-mediated uptake by organic anion transporters expressed in liver and kidney. Special emphasis will be placed on in vitro evidence to support the hypothesis and the complexity confounded by the non-specific binding of the drug-albumin complex. Possible implications to improve the prediction of transporter-mediated hepatic and renal clearance for highly protein bound drugs will be discussed.

Plasma proteins or human serum albumin have been reported to increase the in vitro uptake clearance of highly albumin-bound anionic drugs. Various hypothesis and mechanistic models have been proposed to explain such phenomenon. However, some controversial observations have suggested that possible artifact of the non-specific binding may complicate the data interpretation. This special webinar will be started with two presentations given by the graduate students (their works were presented at the 2022 International ISSX meeting as poster presentations), followed by a panel discussion with all speakers, their scientific mentors, and international renowned experts in transporter field. The knowledge gained from this presentation will help scientists at all levels to learn the concept of albumin-mediated uptake effects by transporters; understand their complexity and current knowledge gaps. The discussion will also provide some insights and practical considerations on designing in vitro transport kinetic studies for highly protein bound drugs to improve their in vitro to in vivo extrapolation. 

Speakers:                                                                                                                                                                                               Mengyue (Melody) Yin, University of Washington, USA                                                                                                                                   Shawn Pei Feng Tan, University of Manchester, UK

Panelists:                                                                                                                                                                                                    Aleksandra Galetin, University of Manchester, UK                                                                                                                                        Jash Unadkat , University of Washington, USA                                                                                                                                              Yuichi Sugiyama, Josai International University, Japan