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Pollastri ACS-2015 CDD Workshop
- 1. ENABLING DISTRIBUTED NEGLECTED TROPICAL DISEASE DRUG DISCOVERY WITH THE CDD VAULT 18 August 2015 - CDD Vision Workshop at the 250th National Meeting of the ACS Michael Pollastri, Ph.D., Department of Chemistry & Chemical Biology Northeastern University 617.373.2703 m.pollastri@neu.edu www.northeastern.edu/pollastri Twitter: @NUTrypKiller
- 2. Overarching mission …to discover at least three high quality lead compounds that can launch partnered preclinical studies for tropical disease therapeutics. Pollastri Lab Hit Compounds Lead Compounds Compounds meet some minimal criteria Compounds meet multiple rigorous endpoints
- 3. Neglected diseases A serious healthcare disparity • NTDs affect 1 billion people, usually the very poor • Total spend in 2011 for 31 NTDs was $3.05 billion – 67% for HIV, TB, malaria, leaving ~$1 bn for 28 NTDs! • New therapeutic outputs are grim: – 1975-1999: 13 out of 1,398 new drugs for NTDs – 2000-2011: 37 out of 850 (4%); 4 NCEs (1%) Little pharma involvement because the “blockbuster model” doesn’t work in this situation Gfinder Report Trouiller et al 2002 Lancet 359:2188-2194 Pedrique et al 2013 Lancet e371 - e379
- 4. 1. DALY = Disability-adjusted life years (years of healthy life lost) from WHO Global Burden of Disease 2004 Update 2. Candidate numbers for cancers only include projects with lung or prostate as primary indication Research is disproportionate to need Disease Pathogen DALY1 (millions) Drugs in the pipeline Tuberculosis 34.7 30 Malaria Plasmodium sp. 34.6 17 Lung cancer2 11.2 77 Leishmaniasis Leishmania sp. 2.3 8 Schistosomiasis Schistosoma sp. 2.1 0 Prostate cancer2 1.6 80 African sleeping sickness Trypanosoma brucei 1.5 4 Chagas disease Trypanosoma cruzi 0.7 1 A main driver of these disparities is the inability of those affected to pay.
- 5. Starting with existing drugs can expedite new discoveries Drug repurposing for NTDs • Eflornithine for HAT • Ivermectin for onchocerciasis • Auranofin for Giardia, Leishmania, Amoeba • Amphotericin B for Leishmania These are approved drugs being re- directed as they currently exist • Potential for toxicity? • Are we settling for what we have, instead of what we could have? Questions • Can we use repurposed drugs as starting points for optimization? • How do we most efficiently select starting points from the current pharmacopeia?
- 6. Target class repurposing • Involves matching of families of targets on the basis of their loosely homologous function • Typically driven by growth phenotype, with confirmation of target(s) later • Examples: – Tyrosine phosphorylation – Lipid phosphorylation • Advantages: – Compounds selected with cellular activity (ie potency plus penetration) – Potential multi-target activity reduces risk of resistance • Issues: – Challenging to drive SAR compared to target-based – More difficult to assess for target selectivity PLoS-Neglected Tropical Diseases 2011, 5, e1297 Journal of Medicinal Chemistry 2014, 57, 4834
- 7. The typical drug discovery paradigm Target class repurposing An approach for streamlining drug discovery ID classes of targets of conserved cell function Match to small molecule inhibitors of homologous human cell function Screen human inhibitors Optimize for parasite activity & desired properties New starting point for anti- parasitic drugs • Toxicity understood • Reuse existing knowledge for optimization • A “privileged” class of compounds • Opportunity to engage pharm collaborators Can these timelines be shortened? Target repurposing entry point Pollastri, M.P; Campbell, R.K. Future Medicinal Chemistry 2011, 3,1307. Pixu Liu, Hailing Cheng, Thomas M. Roberts & Jean J. Zhao, Nature Reviews Drug Discovery 2009, 8,
- 9. A representative project Northeastern UGA (T. brucei) AstraZeneca UGA (T. brucei) WRAIR (L. major) WRAIR (P. fal.) NYU (T.cruzi) WRAIR (P. fal.) NYU (T. cruzi) CRO See Poster MEDI-449 Distributed drug discovery: Collaborative target repurposing accelerates identification of new leads for neglected tropical diseases. Wednesday, 7pm
- 10. Washington U STL Stephen Beverly WRAIR Rick Sciotti GlaxoSmithKline Pepe Fiandor Pili Manzano Julio Martin Gonzalo Colmenarejo David Drewry Bill Zuercher University of Georgia Kojo Mensa-Wilmot CSIC – Granada, Spain Miguel Navarro New York U Ana Rodriguez Southern Methodist Larry Ruben AstraZeneca Peter Webborn Mark Wenlock Kevin Pritchard Seattle Biomed Ken Stuart Marine Biological Lab Bob Campbell Vanderbilt University Galena Lepesheva UC San Diego Jim McKerrow Jair Siqueira-Neto McGill University Reza Salavati Boston University Salomon Amar David Sherr Sandor Vajda Vipul Chitalia Barbara Corkey Beth-Israel Paula Fraenkel UCSF Mike McCune Univ. of Washington Fred Buckner Christophe Verlinde Distributed drug discovery Success via interdisciplinary and industrial collaborations
- 11. A flexible data system was needed Desired criteria – Chemist-proof – Low maintenance – Ability to import/export data easily – Low cost Capabilities – Compound registration – Biological data import – Computed properties – Selective data sharing with public and collaborators outside NEU (Excel is not a data system, by the way)
- 12. Collaborative Drug Discovery A cloud-based solution Courtesy of Collaborative Drug Discovery
- 13. Confidential Knowledge Store Distributed drug discovery A robust data system is required File Share • Models • Slides CDD Vault • Structures • Screening data • ADME data • Public data sets Chemistry Team Chemical structures Biology TeamsScreening Member Lab 3 (Modeling) Models Industrial partners ADME, Tox, selectivity
- 15. Kinases are an excellent target to repurpose The druggable genome Hopkins, AL; Groom, CR. et al. Nat Rev Drug Disc , 2002:727
- 16. Kinases are an excellent target to repurpose The Human Kinome 518 members http://chembl.blogspot.com/2013/09/the-clinical-kinome-in-2013.html The Clinical Kinome in 2013
- 17. Kinases are an excellent target to repurpose Parsons, M. et al. BMC Genomics 2005, 6:127 • Good similarity to human kinases • Target-based approaches of limited success due to lack of detailed functional knowledge Trypanosomatid parasites • 176 T. brucei • 190 T. cruzi • 199 L. major • No receptor or protein tyrosine kinases • Few species-unique genes
- 18. Target repurposing Finding opportunities among kinases Trypanosomatid Kinases • 176 T. brucei • 190 T. cruzi • 199 L. major • No protein or receptor tyrosine kinases • Few species-unique genes lapatinib T brucei EC50: 1.5 μM Parsons, M. et al. BMC Genomics 2005, 6:127 Katiyar, S.; et al. PloS One, 2013, 8, e56150. Kojo Mensa-Wilmot, UGA Observation: Nonspecific tyrosine kinase inhibitors block transferrin uptake in T brucei and impact parasite growth
- 19. Rapid SAR development Diverse boronic acids Systematic truncation 10 analogs 15 analogsSubstituent scan 19 analogs Caitlin Karver, Gautam Patel, NEU Ranjan Behera , UGA J. Med. Chem.2013, 56, 3820.
- 20. Rapid SAR development Diverse boronic acids 44 analogs, 3 cycles Caitlin Karver, Gautam Patel, NEU Ranjan Behera , UGA
- 21. NEU617 as a lead compound NEU-617: Oral Pharmacokinetics – 40 mg/kg plasma brain Ranjan Behera , UGAJ. Med. Chem.2013, 56, 3820.
- 22. NEU617 as a lead compound Ranjan Behera , UGA 105 106 107 108 109 1010 UND U T U T U T U T U T U T T T T T T Parasitemia(trypanosomes/ml) Days Post-Infection U - Untreated Group (Control) T - NEU617 Treated Group */ UND - Parasitemia Not Detected * * * * * * * 2 3 4 5 6 7 8 9 10 11 12 IP Dosing J. Med. Chem.2013, 56, 3820.
- 23. NEU617 as a lead compound NEU-617: Oral Pharmacokinetics – 40 mg/kg plasma brain Ranjan Behera , UGA 0 1 2 3 4 5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 NumberofMiceAlive Days Post-Infection Control NEU617 NEU617 treatment provides 4 day life extension over controls J. Med. Chem.2013, 56, 3820.
- 25. Tier 2 Assays Tier 1 Assays Project workflow Synthesis at Northeastern Registration Ship AstraZeneca UGA (T. brucei) WRAIR (P. fal.) NYU (T. cruzi) CRO Pharmacokinetics Data upload Design UGA (T. brucei) NYU (T. cruzi) WRAIR (Pfal) WRAIR (Lmj)
- 26. Scaffold exploration Strategy – used preferred “head/tail combinations” with various core replacements Matched core replacement analogs for each parasite
- 27. Some scaffolds seem better than others These results set the groundwork for continued optimization efforts for each pathogen
- 28. All looks promising, except… Color: TPSA 46.6-121.4 Å2 Time for a shift in focus from potency to properties
- 29. Improving properties The headgroup is largest and most lipophilic region and has the flattest SAR. NEU961 366 member virtual library 3D shape & electrostatics comparison Properties filter Properties compliant virtual library Polar heterocyclic replacements • Rule-of-5 • MPO • Predicted properties
- 30. Improving properties The headgroup is largest and most lipophilic region and has the flattest SAR. NEU961 366 member virtual library 3D shape & electrostatics comparison Properties filter Properties compliant virtual library Polar heterocyclic replacements
- 31. Improving properties The headgroup is largest and most lipophilic region and has the flattest SAR. NEU961 366 member virtual library 3D shape & electrostatics comparison Properties filter Properties compliant virtual library Polar heterocyclic replacements • Rule-of-5 • MPO • Predicted properties
- 32. Properties-based design: HAT First generation library (109 quinazolines) NEU-617 Tbb EC50 : 0.042 µM Tbb pEC50: 7.37 LogP: 7.31 LLE: 0.06 NEU617-similar, CNS MPO compliant VL (26 compounds)
- 33. Properties-based design: HAT First generation library (109 quinazolines) NEU-617 Tbb EC50 : 0.042 µM Tbb pEC50: 7.37 LogP: 7.31 LLE: 0.06 NEU-1960 Tbb EC50 : 0.288 µM Tbb pEC50: 6.54 LogP: 3.78 LLE: 2.8 Tbb pEC50 LogP NEU617-similar, CNS MPO compliant VL (26 compounds)
- 34. Properties-based design: HAT First generation library (109 quinazolines) NEU-617 Tbb EC50 : 0.042 µM Tbb pEC50: 7.37 LogP: 7.31 LLE: 0.06 NEU-1960 Tbb EC50 : 0.288 µM Tbb pEC50: 6.54 LogP: 3.78 LLE: 2.8 LogP Tbb LLE NEU617-similar, CNS MPO compliant VL (26 compounds)
- 35. Properties-based design: HAT First generation library (109 quinazolines) NEU-617 Tbb EC50 : 0.042 µM Tbb pEC50: 7.37 LogP: 7.31 LLE: 0.06 NEU-1960 Tbb EC50 : 0.288 µM Tbb pEC50: 6.54 LogP: 3.78 LLE: 2.8 Tbb pEC50 LogP LogP Tbb LLE NEU617-similar, CNS MPO compliant VL (26 compounds) Lipophilic Ligand Efficiency (LLE)= pIC50-clogP How much of the potency is due to lipophilicity? Target LLE ≥ 4
- 36. Log P AqueousSolubility(uM) Solubility isn’t driven by lipophilicity Need to address crystal packing energy
- 37. Log P AqueousSolubility(uM) Solubility isn’t driven by lipophilicity Need to address crystal packing energy
- 38. Project status NEU-1912 T brucei EC50 = 24 nM TC50 = >100 uM cLog P: 2.7 Log D: 3.3 LLE: 4.9 Aq sol: 1.42 uM HLM: 207.5 PPB: 94.3% CNS MPO: 4.3 T brucei –properties optimization for improved CNS penetration and solubility 0 1 2 3 4 1 2 3 4 5 6 7 8 9 10 Numberofmice(alive) Days Post-Infection Vehicle NEU1912 (40 mg/kg)
- 39. Project status P. falciparum – quinoline series representatives showed suppression of parasitemia in vivo. Human tyrosine kinase inhibitor chemotypes can be repurposed as antiparasitic leads NEU-1967 L. major EC50: 0.67 μM T. cruzi EC50: 0.06 μM MW = 373 logP = 3.62 Aq sol: 2.6 uM NEU-1953 P. fal EC50: 0.025 μM Aq sol: 43.6 μM PPB: 87.2% HLM Clint: 179 μL/min/mg NEU-1912 T brucei EC50 = 24 nM TC50 = >100 uM cLog P: 2.7 Log D: 3.3 LLE: 4.9 Aq sol: 1.42 uM HLM: 207.5 PPB: 94.3% CNS MPO: 4.3 T brucei –properties optimization for improved CNS penetration and solubility L. major, T. cruzi – NEU-1967 – testing for PK and in vivo efficacy
- 40. ENCOURAGING WIDER DATA SHARING IN NTD DRUG DISCOVERY
- 41. Increasing efforts in this space! Publically available compound screening data for tropical diseases eg. ChEMBL-NTD, CDD Public, PubChem NTD drug discovery Front-loaded with immense quantities of hit matter Hit Compounds New Candidates for NTDs Hit and Lead Optimization Key questions • Who is working on what compounds/parasites? • What has been done? • What has failed? • Are there gaps? • Are the endpoints the same? • Is data being fed back into these data sources? ? www.ebi.ac.uk/chemblntd www.collaborativedrug.com pubchem.ncbi.nlm.nih.gov Prod Devt Partnerships Contract Orgs Industry NonprofitsAcademics Gov’t labs Isn’t this really a large, uncoordinated, distributed drug discovery program?
- 42. Increasing efforts in this space! Publically available compound screening data for tropical diseases eg. ChEMBL-NTD, CDD Public, PubChem NTD drug discovery Front-loaded with immense quantities of hit matter Hit Compounds New Candidates for NTDs Hit and Lead Optimization ? www.ebi.ac.uk/chemblntd www.collaborativedrug.com pubchem.ncbi.nlm.nih.gov Prod Devt Partnerships Contract Orgs Industry NonprofitsAcademics Gov’t labs Isn’t this really a large, uncoordinated, distributed drug discovery program? This is a GREAT thing, but let’s not waste efforts with unknowing duplication and unrealized synergies!
- 43. Initiative MembersConfidential Knowledge Store A “hybrid” open model of discovery File Share • Models • Slides CDD Vault • Structures • Screening data • ADME data • Public data sets Member Lab 1 (Chemistry) Chemical structures Member Lab 2 (Biology) Screening Member Lab 3 (Modeling) Models Industrial partner (data) ADME, Tox, selectivity Targeted Product Profiles for each pathogen Resources for key tasks Stakeholders (DNDi, MMV etc) Public data Currently Recruiting Participants! www.neu.edu/pollastri/collaborate
- 44. Initiative MembersConfidential Knowledge Store A “hybrid” open model of discovery File Share • Models • Slides CDD Vault • Structures • Screening data • ADME data • Public data sets Member Lab 1 (Chemistry) Chemical structures Member Lab 2 (Biology) Screening Member Lab 3 (Modeling) Models Industrial partner (data) ADME, Tox, selectivity Targeted Product Profiles for each pathogen Resources for key tasks Stakeholders (DNDi, MMV etc) Public data Currently Recruiting Participants! www.neu.edu/pollastri/collaborate Ground rules • All data in the vault is a confidential disclosure to consortium members. • Participants must disclose all their data (including structures) in real time. • There will be no lurking. We are not… • Trying to coordinate or consolidate efforts, only to inform them • Forcing collaborative efforts • Looking to rip anyone off.
- 45. CDD Vault Enabling the Hybrid-Open discovery efforts • Easy to add collaborators for data sharing and control access • We had created a new Vault for data sharing. – However, now CDD users can perform searches across Vaults! Currently Recruiting Participants! www.neu.edu/pollastri/collaborate
- 46. Summary • Neglected Tropical Disease Drug Discovery can benefit from repurposing existing leads and drugs from other indications, followed by re-optimization for NTD-specific needs – Kinase inhibitors, in particular are excellent for this purpose • Working in drug discovery in an academic environment requires engagement of a variety of expertise, often outside the institution. • Harnessing these capabilities requires a sturdy and flexible data handling solution • CDD Vault has enabled seamless data sharing, computation and visualization within our collaborations
- 47. Our Research Lab Research Scientists Dr. Seema Bag Dr. Takashi Satoh Dr. Daljit Matharu Postdoctoral Associates Dr. Lori Ferrins Dr. Baljinder Singh PhD students Kelly Bachovchin Dana Klug Naimee Mehta Undergraduates Travis DeLano Vivian Hilborne Group Alumni Dr. Emanuele Amata Dr. Trent Ashton Dr. David Finnegan Dr. Caitlin Karver Dr. Adam Lesser Dr. Sandra Luongo Dr. Gautam Patel Dr. Joao Seixas Dr. Cuihua Wang Dr. William Devine Dr. Stefan Ochiana Dr. Zhouxi Wang Dr. Jennifer Woodring Zeke Clements, MS Elizabeth Jones, MS Lisseth Silva, MS Cheri Snedeker, MS Uma Swaminathan, MS Angela Tanner, MS Joel Beatty Emily Blazensky Peter Edwards Stephen Ejk Tim Hopper Cristin Juda Michael Russo Katherine Spring Matthew Stevenson Craig Tallman Anthony Varca Funding & In-Kind Support R01 AI082577 R01 AI114685 R56 AI099476 GlaxoSmithKline OpenLab Foundation Flatley Discovery Labs Astra Zeneca Pfizer, Inc GSK OpenEye Scientific Software ChemAxon CDD
- 48. Michael Pollastri, Ph.D., Department of Chemistry & Chemical Biology Northeastern University 617.373.2703 m.pollastri@neu.edu Lab website: www.northeastern.edu/pollastri Twitter: @NUTrypKiller Global Health Initiative: www.northeastern.edu/globalhealth