patients

LEISHMANIASIS
R&D MODEL & PORTFOLIO
RESEARCH
Leish H2L
(Leishmaniasis Hit to Lead)
PROJECT START: On-going
OVERALL OBJECTIVE: Identify new leads series from current
ongoing Hit-to-Lead activities by taking advantage of the
optimization consortia platform screening of compounds for VL
2015 OBJECTIVE: Progress two new chemical classes into lead
optimization
Hit to lead is a dynamic phase in the drug discovery cascade
in which small molecule hits from high throughput screens
are evaluated and undergo limited optimization to identify
promising lead compounds. Series from a number of different
partners have shown activity against L. donovani; work on
these series to bring forward suitable candidates for lead
optimization is on-going.
Oxaborole
(previously known as Oxaleish)
PROJECT START: January 2010
OVERALL OBJECTIVE: Select an oxaborole for pre-clinical
evaluation
2015 OBJECTIVES:
• Select an oxaborole for pre-clinical evaluation
• Complete profiling of lead oxaboroles
DNDi and Anacor have been working together over the last
few years to identify oxaborole compounds, initially for the
HAT programme, and this has expanded to include both
leishmaniasis and Chagas disease. DNDI-6148 has emerged
as a promising lead candidate and by the end of 2015, studies
including exploratory toxicology necessary for possible
progression to pre-clinical development had been successfully
completed. It is anticipated that pre-clinical development of
DNDI-6148 will commence following a review meeting in January
2016. Approximately four additional oxaborole compounds
continue to be developed behind DNDI-6148 as potential backups
in case an insurmountable issue should be identified.
MAIN PARTNERS: Anacor Pharmaceuticals Inc., USA; Laboratory
of Microbiology, Parasitology and Hygiene, University of Antwerp,
Belgium; London School of Hygiene and Tropical Medicine (LSHTM),
UK; Wuxi AppTech, China; Sandexis, UK
Aminopyrazoles
A notable success in January 2015 was the successful
advancement of the aminopyrazole series from the hit to lead
stage into the next lead optimization stage. This early work
has recently been published in J. Med. Chem. In addition, the
NTD Drug Discovery Booster project commenced in April
2015 working with four pharmaceutical companies: Eisai,
Shionogi, Takeda, and Astra Zeneca and has so far conducted
hit expansion on six different hits which are being developed
for leishmaniasis and Chagas disease.
A number of pharmacokinetic and pharmacodynamic studies
have been conducted in animal models of VL using existing
and experimental drugs to build improved PK/PD models
and ameliorate the translation of new drugs from discovery
into clinical studies.
MAIN PARTNERS: Epichem, Australia; UNICAMP (University of
Campinas, Brazil); Centre for Drug Candidate Optimization, Monash
University, Australia; TCG Lifesciences, India; Sandexis, UK; WuXi
AppTech, China; Laboratory of Microbiology, Parasitology and
Hygiene, University of Antwerp, Belgium; London School of Hygiene
and Tropical Medicine, UK; Griffith University, Australia; GSK, Tres
Cantos, Spain; Sanofi, France; Anacor Pharmaceuticals Inc., USA;
Merck, USA; AstraZeneca, UK; AbbVie, USA; Pfizer, UK.
PROJECT START: February 2012
OVERALL OBJECTIVE: Select an aminopyrazole for pre-clinical
evaluation
2015 OBJECTIVE: Identify compounds suitable for pre-clinical
evaluation
Compound mining of well-annotated chemical compound
libraries has been used to identify a new class of compounds
active against VL. In June 2014, the first in vivo proof of
concept for VL series 12 (aminopyrazoles) from Pfizer was
achieved in the hamster early curative model of VL. An initial
compound gave 93% and 95% reductions in parasitaemia
in liver and spleen respectively after five days oral dosing
at 50mg/kg BID, with a subsequent compound showing
even better in vivo activity (>99% reduction in parasitaemia
in both liver and spleen). The project moved into the lead
optimization stage in January 2015, with GHIT Fund support
and expert scientific assistance from Takeda from April 2015.
Further compounds are being designed and tested. Profiling
of current and new leads in a panel of drug sensitive and drug
resistant strains of Leishmania, exploration of the in vivo dose
response, rat pharmacokinetics, and initial in vitro safety
assays are all underway. A full lead optimization programme
is ongoing and we aim to select an optimized lead in 2016.
MAIN PARTNERS: Takeda Pharmaceutical Company Ltd, Japan;
Wuxi AppTech, China; Laboratory of Microbiology, Parasitology and
Hygiene, University of Antwerp, Belgium; London School of Hygiene
and Tropical Medicine, UK; Pfizer, UK; Sandexis, UK
DNDi Annual Report 2015 › 29