David Barros-AguirreTB DPU, GSK

Mtb LeuRS inhibitors

GSK070 update

WC Non replicating:

GSK’677-TBDA

TB DPU: Global portfolio of Projects

The power of collboration under open innovation

WC Replicating Mtb

(0.5M Screen)

Anacor (Prot. Synth)

Mtb LeuRS B-up Mtb LeuRS

(Prot .synth)

Indazole series

(Mtb KasA)-GATB

HTS/MTS Hit2Lead Lead OpPre-

ClincalFTIM

Phase IIa

InhA

Thiadiazole-EU FP7

WC Non- replicating

Mtb

(0.5M Screen)-TBDA

EU FP-7

BROAD Collection

In vivo screening

(2 H2L)

DprE1 (Cell wall)

GSK’710 -GATBMtb KasA

HTS/ELT/FBDD

DprE1 (Cell wall)

GSK’540 -TBDA

WC Hit2Lead

3 series GATB

Wellcome Trust

B-lactams -EDCTP

Diacon@Stellenbosch

IL4

Paton@NUS>

Investigator LedAspRS Mtb

Besra@UoB

Cyclodepsipeptides

Imming@Halle

Mtb Macrophage HTS

Av-Gay@UBC

WC Mtb cond. mutants

Schappinger@WCMU

Intracellular Hits

Pethe@IPK

B-lactams synergy

Ramon@UBC

TCOLF, External PI

Color coding

WC Hit2Lead

2 series WT

Bioversys (WT)

Ethionamide boosters

B-lactams

Paton@NUS

A collaborative effort for the discovery of a NCE for TB treatment

Mtb LeuRS inhibitors based on Boron chemistry

Inhibition of LeuRS by Oxaborole tRNA Trapping

(OBORT) in nonproductive editing conformation

– AN2690, a novel pharmacophore, traps tRNALeu in editing site preventing its

aminoacylation, which ultimately leads to a block in protein synthesis

Leucinein

Synthesis Site

AN2690-A76 covalent adduct

In Editing Site

tRNALeu

LeuRS

Co-crystal structure of LeuRS-tRNALeu

from the G(-)-bacterium

Thermus thermophilus

Rock & Mao, et al, Science (2007) 316: 1759-1761.

GSK’147 : acute murine TB model dataPreliminary PK/PD data

1 10 100 1000

0

2

4

6

8

Administration days 1-8 after infection

Acute assayC57BL/6, H37Rv

Infection 10e5 CFU

Lung CFU count on day 9

Inoculum

Limit of detection

every 48h

bid

uid

Dose (mg/kg)

log

CF

U/m

ou

se

Untreated mice

ED99= 0.6 mg/Kg, uid

ED99< 1.0 mg/Kg, 48h

ED99= 1.7 mg/Kg, 96h

•Potent compound at low doses

•Potential for alternate dosing

“All animal studies were ethically reviewed and carried out in accordance with Animals (Scientific Procedures) Act 1986 and

the GSK Policy on the Care, Welfare and Treatment of Animals.”

0 .1 1 1 0 1 0 0

0

2

4

6

8

2 lo g C F U

re d u c tio n

lim it o f d e te c tio n

e v e ry 4 8 h

b id

u id

D o s e (m g /k g )

log

CF

U /

mo

us

e

G S K 2 9 1 2 1 4 7 p o

GSK’147

GSK070 is active against TB in vivomouse and marmoset models

“All animal studies were ethically reviewed and carried out in accordance with Animals (Scientific Procedures) Act 1986 and

the GSK Policy on the Care, Welfare and Treatment of Animals.”

102 cfu/mouse

IntratrachealCFU count

1 day wash out,

lung extraction

6 week

Treatment 16w, uid

Chronic murine model 89C57BL6

GSK070 (G) regimes are superior

to current TB SOC and regimes

under clin development after 4W

Rx in TB infected mice (chronic)

– Pa: Protomanid

– J: Sirturo

– L: Linezolid

PaJL G

GSK070 nonclinical profile

7

– Excellent physicochemical properties (DCS I).

– Novel target and MoAinhibition of protein synthesis by blocking Mtb leucyl t-RNA synthetase (LeuRS)

– Selective antitubercularMIC90 = 0.08 uM (DS, M(X)DR-TB. MIC> 32uM (Mtb vs. other bacteria)

– No cross-resistance to TB drugs, equally active against M(X)DR-TB isolates

– Bacteriostatic activity in vitro, but cidal in vivo (next slide) at low doses -- Acute mouse model: 3 logs reduction in bacterial load after 8 days @1 mg/Kg

- Chronic mouse model: >2 logs reduction in bacterial load after 2 months @1 mg/Kg;

slow initial response

– No safety issues precluding development. GLP tox 28 days

– Projected low human dose (<200mg/day) with a low potential for DDI

Phase 1

FTIH

(SD/RD/FE)

Phase 2a (PoC)

MonoRx

DS TB

(2 w)

Phase 2b/3

Dose ranging

DS/MDR TB ( >2 mo)

NCE added to BR

Drafted development plan to phase 2b/3 for GSK070

ComboRx

DS TB

(1-2 w)

Next Gen EBA*

(Early Bacteriocidal Activity)

A collaborative effort for the discovery of a

NCE for TB treatment

I. Giordano, J. Rullas, I. Angulo-Barturen, L. Guijarro,E. Perez, E.M. López, M.T. Fraile, H. Rami, F. Ortega, S. Crouch, R. Gomez, L. Alameda, S.L. Turner, S. Ferrer, S.L. Gresham, R.J. Lincoln, S.A. Robinson, P.B. Bushdid, C. Alemparte, E. Jimenez-Navarro, G. Derimanov, D. Barros-Aguirre

X. Li, V. Hernandez, F.L. Rock, W. Choi, Y.S.L. Mak, M. Mohan, W. Mao, Y. Zhou, E.E. Easom, V. Ciaravino, J.J. Plattner, M.R.K. Alley

especially

W. Zou

especially

A. Palencia S. Cusack

E. Nuermberger group

K . MdluliN. Fotouhi

M.S. Jimenez

C. Barry, L. Via and H. Boshoff

Thank You