1. 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

2. 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
WC Hit2Lead
3 series GATB
WCS (TrpA)
GSK982-GATB
IL4
WC Replicating Mtb
(0.5M Screen)
B-lactams
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
Cyclodepsipeptides
GSK’286
Cholesterol dependant
GSK
TBDA
WC Mtb cond. mutants
Bioversys (WT)
Ethionamide boosters
EU FP-7
Mtb Macrophage HTS
H2L on Mtb macrophage
WCS (WT)
TrpA Series (B)
Wellcome Trust
Investigator Led

3. 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 ( )
Discovery of a NCE
New, oral and low dose
FTIM (1Q 2017)

4. 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

5. 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

6. 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:

7. 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