Tuberculosis DPU portfolio

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Tuberculosis DPU portfolio GSK DDW Tuberculosis DPU portfolio WGND side meeting,47th Union World Conference on Lung Health, David Barros Aguirre TB DPU, Tres Cantos GSK DDW

TB DPU Global portfolio of Projects: GSK+ External Collaborations HTS/MTS Hit2Lead Lead Op Pre-Clincal FTIM Phase IIa Mtb KasA HTS/ELT/FBDD DprE1 (Cell wall) GSK’540 -GATB B-lactams -EDCTP Diacon@Stellenbosch WC Hit2Lead 3 series GATB WCS (TrpA) GSK982-GATB IL4 Paton@NUS> WC Replicating Mtb (0.5M Screen) B-lactams Paton@NUS WC Non- replicating Mtb (0.5M Screen)-TBDA WC Non replicating: TBDA Mtb LeuRS B-up (GSK830) Mtb LeuRS (GSK656) b-lactams for TB Color coding B-lactams synergy Ramon@UBC Cyclodepsipeptides Imming@Halle GSK’286 Cholesterol dependant GSK TBDA WC Mtb cond. mutants Schappinger@WCMU Bioversys (WT) Ethionamide boosters EU FP-7 Mtb Macrophage HTS Av-Gay@UBC H2L on Mtb macrophage Av-Gay@UBC WCS (WT) TrpA Series (B) Wellcome Trust Investigator Led

Clinical repurposing (2017-2021) TB Pipeline. Advanced Projects From Repurposing old drugs to the discovery of new chemical entities Focused on the discovery of new clinical candidates for the treatment of multidrug resistant TB In house expertise on novel imaging techniques and animal models Source of projects: phenotypic hits, target based and new mechanisms of action Repositioning b-lactams for MDR-TB Rapidly citocidal, safe and approved for children AnTBiotic Consortium Clinical repurposing (2017-2021) Discovery of a NCE New, oral and low dose FTIM (1Q 2017)

GSK070 Mtb LeuRS inhibitor A novel protein synthesis inhibitor with a new MoA GSK070 Murine model Marmoset model Mtb MIC H37Rv < 0.1 uM THP-1 Mtb MIC < 0.1 uM Selective antitubercular Mtb MIC= 0.08uM vs MIC> 32uM (other bacteria) Active in vivo in acute and chronic TB models (murine and marmosets) Projected low human dose <<200mg/day (oral) GLP tox completed (1mo rat &dog): Good Therapeutic Index Next Milestone: Commitment to Entry into Man (4Q2016) 4

β-lactams as a source of novel anti-tuberculars Successful progression of b-lactam combination to clinical POC Andreas H Diacon, Lize van der Merwe, Marinus Barnard, Florian von Groote-Bidlingmaier, Christoph Lange, Alberto L García-Basteiro, Esperança Sevene, Lluís Ballell and David Barros-Aguirre. New England Journal of Medicine 15-13236

Company Compound Libraries The TB Drug Accelerator The TBDA is a groundbreaking collaboration between eight pharmaceutical companies, eight research institutions, and a product development partnership to facilitate early TB drug discovery. How it works… new preclinical candidates 2019 Collaborative Discovery Research Company Compound Libraries Hit and Lead Generation Target Identification 1 month regimen proof of concept 2024 Lead Optimization With Participation From:

H2L & LO Program Diversity as the key Protein synthesis inhibition/Mtb Tryptophan Synthase Decaprenylphosphoryl-D-ribose oxidase inhibition (DprE1) KasA Static in vitro behavior confirmed. Trp rescue is dramatically diminished for intracellular bacteria. TS inhibitors are now validated in acute and chronic in vivo assays Old series with good properties but issues regarding the human dose prediction New series with divergent SAR as potential back up Previous series terminated due to mutagenic metabolite risk. Target based screening campaign achieved