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2017 Drug Design and Delivery Symposium “Psoriasis: Treatment and Novel Approaches”
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The discovery of AZD0284, an inverse agonist of the nuclear receptor RORg Frank Narjes, Dr. rer. nat. Respiratory, Inflammation and Autoimmunity IMED Biotech Unit AstraZeneca, Gothenburg, Sweden
American Chemical Society, 2017 Drug Design and Delivery Symposium
26 October 2017
Outline
Introduction
Discovery of AZD0284
Pharmacology and PK / PD
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Challenge Question ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
Estimate the prevalence of Psoriasis in North America and Europe: • Less than 1 percent • About 1 percent • About 2 percent • About 5 percent • About 10 percent
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Psoriasis Pathogenesis – Current understanding • Psoriasis is a non-contagious chronic disease (Boehncke The Lancet 2015) - Probably initiated by environmental insults combined with genetic predispositions
• Immune system causes keratinocyte hyperproliferation - skin cells pile up, causing painful, itchy, red, scaly patches
• Major impact on quality of life; prevalence of ~2% in North America and Europe • Increased risk of comorbidities such as psoriatic arthritis, cardiovascular disease or IBD TH17 cells have a key role in sustaining the chronic inflammation
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Anti TH17 agents show strong efficacy in plaque psoriasis
Lynde et al. J. Am. Acad. Dermat. 2014
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The IL-23 / IL-17 axis in autoimmune disease • TH17 cells orchestrate host defense in response to Candida and Mycobacteria - Induced downstream of IL-23 • TH17 cells are important drivers of chronic inflammation in immune-mediated diseases such as plaque psoriasis, psoriatic arthritis and ankylosing spondylitis naïve CD4+ T cell
TH17 cell
Target tissue CCR6high
Th17
TGFb IL-1b IL-6 IL-23
IL-23R
Th1 RORg/γt CD4 CD3
7
Ustekinumab
IL-22 IL-17F IL-17A
Psoriasis Th17 RA MS IL-17R
Secukinumab Cosentix®
Brodalumab
• Antibodies targeting the IL-23 / IL-17 axis show impressive clinical efficacy • RORgt is essential for TH17 cell development and differentiation 21
Miosecc, Kolls Nat. Rev. Drug Disc. 2012
Challenge Question ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
What proportion of small molecule drugs have nuclear receptors as their target? • About 5 percent • About 10 percent • About 15 percent • About 20 percent • Almost 25 percent
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Retinoic Acid Related Orphan Receptor (ROR) • Nuclear receptor superfamily; a, b, g forms • Intracellular receptors; regulate gene expression • About 15% of small molecule drugs target NR’s
• RORg : 2 isoforms with identical LBD • RORgt expression restricted to immune cells • RORg expressed in many tissues
• Constitutively active orphan receptors • Cholesterol derivatives proposed as ligands • Bind in large hydrophobic binding pocket
• Activity can be modulated by small molecules • Modulates conformation of helix 12 / AF2
• RORgt has a central role in T-cell development • Loss of RORgt leads to reduction in mature T-cells (mice 80%, human 50%) Safety concerns • Lymphoma develops in embryonic and conditional KO-/- mice (Ueda 2002; Liljevald 2016)
• Thymic aberrations observed with potent inhibitor in 3-month tox study (Guntermann 2017) Human KO show no sign of haematological malignancies (Okada 2015)
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RORg is centrally positioned for efficacious treatment Inhibiting RORg/gt has the potential to surpass single cytokine neutralising antibodies
CCR4
• Induced downstream of IL-23 • Required for the expression of IL17A and IL17F, and partly IL-22
T H17
RORg/gt IL-23
IL-17A IL-17F IL-22
IL-23R
• Upregulates expression of the IL-23 receptor IL-12
RORg required for other IL-17 producing cells • Pathogenic TH17/TH1 cells
Pathogenic TH1/TH17 cell CXCR3
- express IL-17, IFN-g, MDR1 and high levels of IL-23R
• Innate lymphoid 3 cells (ILC) and gT-cells
T H1/T H17 RORg/gt T-bet
IL-23
MDR1 IL-17A IFN-g
IL-23R Plasticity of TH17 cells: Bailey Frontiers Immun. 2014 Pathogenic TH17 cells: Ramesh J. Exp. Med. 2014
Objective: Develop oral RORg inverse agonists for the treatment of TH17 driven diseases 24
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Discovery of AZD0284
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Hit finding strategy • Knowledge-based approach
• FBLG
- Characterise literature compounds - Focussed screen on known motifs
• HTS
- Fragment X-ray screening produced multiple hits
- 2 clusters identified
Obtain X-ray structures to support SBDD
Phenex
Scripps
T0901317
Lycera
GSK
Fauber J. Med. Chem. 2014 Kamenecka MedChem Comm 2013
•
X-ray structures in 2 different constructs
Xue et al. ChemMedChem 2016
•
Digoxin Inverse Agonist
Cell assay in primary human TH17 cells - Cells isolated from healthy donors, 384 well plates Inhibition of IL-17 production and cell viability
• agonist and native construct
• Used for DtM prediction
His479
CCR6
CD4 CD3 26
Fujita-Sato S et al. J. Biol. Chem. 2011
TH17
START DAY 0
- Compounds - TH17 polarizing cytokines - Stimuli (anti CD3 anti CD28 beads)
Incubate
STOP DAY 4
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Early SAR
Helix5 R364 R367 S404 Helix7
Large binding pocket with hydrophobic core SPA pIC50
Q286 F377
8.6
FRET pIC50 (%)
7.7 (-82)
Cell pIC50 (%)
8.2 (-85)
Polar interactions in binding pocket
*
SPA pIC50 FRET pIC50 (%) Cell pIC50 (%)
7.7
Complete loss of cell potency
7.5 (-84) 100 ↓
Phe378
*
Glu379
*
Cell pIC50 (%)
7.6 (-72)
7.2 (-60)
LogD pH 7.4
>4
>4
Sol. (amorph., mM)
0.7
0.1
HLM Clint (mL/min/mg)
31
9
Rat PK: t1/2 (h), F (%)
1.4, 3
4.6, 36
Target polar interactions + Identify other functional triggers
29
Extensive structural modifications Target polar interactions in sub-pocket
*
*
*
*
Cell pIC50 (%)
7.2 (-79)
logD pH 7.4
3.8
Sol. (mM)
205
Search for alternative functional triggers
*
*
Cell pIC50 (%) logD pH 7.4 30
Sol. (mM)
7.0 (-64) >4 0.1
*
()
*
*
*
Cell pIC50 (%)
6.7 (-86)
logD pH 7.4
3.5
Sol. (mM)
53
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Combination leads to better properties
Helix7 TH17 cell (pIC50, %)
7.2 (-79)
7.5 (-95)
Ser404
Sol. (mM) / logD7.4
205
381
3.1
RORa FRET (Ag. / inv. Ag)
