Compound Re-Profiling. Dr Robert Scoffin CEO, Cresset

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1 Compound Re-Profiling Dr Robert Scoffin CEO, Cresset

2 What is it? F F F N N H 2 N S O O Br > Compound Re-Profiling or Re-Purposing is the process of finding a new clinical use for an existing treatment > Re-Profiling has been done for years, but on an ad hoc basis often resulting in off-label prescription for new indications > Cresset s technology and applications enable a deeper understanding of actual drug activity and allow the prediction of likely activity for other compounds > Leading to an in-silico basis for compound re-profiling

3 Advantages - Why do it? > Classical drug discovery and development is getting harder > Rising development cost > High rates of attrition due to toxicology, lack of efficacy, lack of market > Increasingly stringent regulatory demands > Difficulty in recouping R&D spend > Many key products reaching patent cliff s

4 Advantages > In the main, the advantages are based on greater knowledge of agent compared to classical NCE discovery (toxicology, clinical safety, pharmacokinetics) > Less likely to fail from Tox, Clinical Safety, ADME > Potential for rapid approach to POC > Early kill points: fail early-fail cheap > Maintain markets through new patents > Can be a faster approval process > Commercially valuable? > Highest selling Pharmaceuticals in USA > Nexium (single enantiomer Omeprazole) - 2 nd highest > Adavir(Inhalation combo Salmeterol & Fluticasone) - 4th highest > Sildenafil: hypertension ED, Raloxifene: Breast Cancer Osteoporosis, Milnacipran: antidepressant fibromyalgia & etc..

5 Cresset Re-Profiling Approach > In Cerebro plus In Silico > Human Skills > Pharmacology identify and validate re-profiling opportunities based on known pharmacology. > Biology identify interesting areas of novel biological understanding, leading to new pharmacology opportunities > Computational Chemistry analyse known information on compounds and mechanisms propose long list of compounds for screening > Medicinal Chemistry validate and filter long list to short-list to be purchased and screened

6 Cresset Re-Profiling Tools > Forge > Templating of known actives to form an understanding of bioactive conformation (in the absence of crystal structure) > Modelling, alignment and analysis (SAR, QSAR) of known actives to derive understanding of key binding features and interactions > High content virtual screening of candidates > Blaze > High throughput virtual screening of candidates

7 Example1 BACE-1 > Beta-site APP Cleaving Enzyme 1 > Aspartyl protease also called beta-secretase > Role in the formation of myelin sheaths around neurons > Cleaves Amyloid Precursor Protein, which can be further cleaved by gamma-secretase, leading to the formation of beta-amyloid peptides, which can form plaques in e.g. Alzheimer s disease > Blockage of BACE-1 has been assumed to be a potential route to preventing or slowing the progression of Alzheimer s Disease (as yet this has not been proven clinically) > Project funded as a proof-of-concept through a UK Government grant (1 year, 200k).

8 Example 1 BACE-1

9 Example 1 BACE-1

10 Post Facto Analysis of Hits > Based on 3D QSAR model built from known BACE inhibitors extracted from the PDB > Closantel pic50 = 8.2 (3 rd highest prediction from database of 800 known drugs) > Epalrestat pic50 = 6.9 (within top 20% of predictions)

11 Example 1 BACE-1 > On the basis of in silico screening, 80 compounds selected from a sub-set of known drugs (sub-set selected pragmatically based on availability of the API for screening) > Initial % Inhibition screen, with IC50 follow-up for any observed hits. > 5 compounds passed the % Inh cut-off > 2 Compounds confirmed with IC50 of c. 16 μm

12 Not one to develop further! Anti-helminthic Low-solubility Poor starting point for drug development N Cl Cl NH I O OH I

13 Not one to develop further! Aldose reductase inhibitor Targeted for diabetic neuropathy Good starting point for NCE development Very poor IP position S O S N OH O

14 Example 2 Annexin A1 > 40kDa Ca 2+ dependent phospho-lipid binding protein, which is a key protein involved in modulation and control of the major human inflammatory mechanisms > Annexin A1 is the main mediator of the glucocorticoid steroid activity in controlling inflammation > ANX-A1 also inhibits the NF- k B signalling pathway leading to a theoretical role as an anti-cancer treatment

15 Scientific Rationale Annexin-A1 & Glucocorticoids GC GR active GR inactive ANX-A1 Inactive Protein Kinase C ANX Phosphorylation &Translocation ANX-A1 activeanti-inflammatory

16 Annexin-A1 (Lipocortin-1) Roles in a broad range of indications Inflammation > Inhibition of PLA2 - attenuation of inflammatory eicosenoid/cytokine pathway > Inhibition of leucoyte migration > Human ANX-A1 effective in animal models of inflammation > Key to GC function Cancer > ANX-A1 mimics anti-inflammatory activity of GC s > In ANX-A1 KO s,gc s are ineffective in animal inflammation models > In Rheumatoid Arthritis impaired induction of ANX-A1 by GC s > Suggested to be apoptotic signal > Under-expression observed in human cancers (eosophageal, prostate, head and neck)

17 Re-Profiling Approach Identification of mechanism of action for existing anti-inflammatory drugs with hitherto unknown mechanism. Identification of novel enzyme target Assume existing drugs work through inhibition of this novel target Confirm the assumption and use existing molecules as starting point for virtual screening In cerebro and in silico identification of small screening set (16 compounds!) Inhibition assay showed excellent activity for one of the compounds Confirmation of activity in cellular and functional assays Identified molecule is an existing oral drug, given for systemic conditions Well tolerated, good safety profile BUT, need to identify open IP space topical applications? Compound also represents a good starting point for further medicinal chemistry to develop NCE s

18 Identification of RP0217 as an inhibitor 6 RP Standard (control) Potent inhibition in the nanomolar range

19 Validated activity in Human Mast cellsstimulated with IgE RP0217 reduces inflammatory signals (histamine and PGD 2 ) with nanomolar potency and increases ANX-A1 release over the same concentration range consistent with the proposed mechanism of action.

20 Summary and Identification of Allergic Conjunctivitis as an initial Therapeutic target > Identification of RP0217 > nm activity at PP2A > nm activity on release ANX-A1 > Potent anti-inflammatory activity in human cells confirmed in fresh blood basophils > Observation of clear potentiation of steroid activity in human cell lines > Animal model of allergic conjunctivitis shows excellent results with equivalent efficacy to known agents > These data confirm the potential of RP0217 as a candidate for development of a novel antiinflammatory and potentially cancer therapeutic agent > Potent and rapid onset of effect > Steroid like activity without steroid safety concerns > Synergy with steroids - reduction of steroid dose for enhanced safety ( Steroid Sparing ) > These data also act as a confirmation of the Cresset principle of smart reprofiling

21 Summary > Successful examples of smart re-profiling > Cresset tools + human expertise == great platform for re-profiling existing compounds for new disease indications > Lowered cost, lowered risk of failure == better chance of market launch

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