Human health. Molecular mechanisms of biological systems. Teaching at. Research at. Brandeis University. Marine Biological Laboratory

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1 Human health Molecular mechanisms of biological systems Research at Marine Biological Laboratory Bay Paul Center for Comparative Molecular Biology and Evolution Woods Hole, MA Teaching at Brandeis University Bioinformsatics Program Rabb School Waltham, MA

E.R. Squibb - Clinical Programs 1 st in class and

Captopril (Capoten) Ph2-3 Fosinopril (Monopril) Ph 1-2

bacterial infecion (Monobactam) Aztreonam (Azactam) Ph

PravastaIn (Pravachol) Ph 1-3 Nocardia autotrophica

2 E.R. Squibb - Clinical Programs 1 st in class and followers Hypertension, Heart Failure (ACE inhibitors) Captopril (Capoten) Ph2-3 Fosinopril (Monopril) Ph 1-2 Zofenopril (Zofenil) Ph st in class gram(- ) bacterial infecion (Monobactam) Aztreonam (Azactam) Ph nd in class Hypercholesteremia (StaIn) PravastaIn (Pravachol) Ph 1-3 Nocardia autotrophica from eucalyptus forest soil, lake-side sand collected at Canberra, Australia.

3 Comparative Genomics of Drug Targets Human and Pathogen Giardia lamblia genome analysis reveals multiple drug target homologs (e.g., TOR, ERK) Question: Can drugs against human targets including failed drugs be a path to drugs vs pathogens?

4 Infectious diseases have major impact

5 What are the Needs for global infectious disease drug discovery? (defined by WHO)

6 Existing Drugs for African Trypanosomiasis are Inadequate

7 Neglected Drug Pipelines Disease DALY 1 (millions) Approximate Number of Candidates (data from Pharmaprojects V5.2 + ClinicalTrials.gov accessed 13 Nov 2008) PCD 2 Phase I Phase II Phase III Tuberculosis Malaria Lung cancer Leishmaniasis Schistosomiasis Prostate cancer African trypanosomiasis Chagas disease DALY = Disability-adjusted life years (years of healthy life lost) from WHO Global Burden of Disease 2004 Update 2. PCD = Preclinical Development 3. Candidate numbers for cancers only include projects with lung or prostate as primary indication

chemistry / structure-activity optimization ADME optimization e.g.

8 Situation for new drugs vs pathogens Valley of Death limits progress Valley of Death = Attrition from hit to clinical candidate Medicinal chemistry / structure-activity optimization ADME optimization e.g., to achieve oral dosing, metabolic stability Safety pharmacology Toxicology

9 Could repositioning of known clinical candidates help bridge this gap?

10 Failed drugs are not all bad Drug Failed Indication Successful Indication Eflornithine cancer sleeping sickness Eflornithine target is Ornithine decarboxylase Conserved between human and trypanosome

Failed discovery projects have value Failed projects oral renin inhibitors Successful follower projects HIV protease inhibitors HIV drug discovery success built from repositioning of expertise from

11 Failed discovery projects have value Failed projects oral renin inhibitors Successful follower projects HIV protease inhibitors HIV drug discovery success built from repositioning of expertise from renin and other aspartyl proteases 1985 HIV genome sequenced 1988 Protease validated as target 1990 first clinical candidates (and eventual drugs) HIV protease (PDB 2NMW - white & red) aligned with human renin (PDB 2V10 - green)

12 Strategy to refill neglected pipelines Drug discovery molecules & expertise can be repositioned to related targets Facilitate identification of industry repositioning candidates via sequence::compound associations Government investment genomes, pathogen biology, disease models for Neglected Disease Pathogen target + drug-like compounds compounds, target chemistry for Other Diseases Industry investment Validate link; Validate target; Tool compounds for in vitro/in vivo testing Focus partnering efforts for Neglected Disease (BVGH, DnDi, direct to industry)

Known drug targets matched to interacting compounds MGKNKLLHPSLVLLLLVLLPTDASVSGKPQYMVLVPSLLH... MESESESGAAADTPPLETLSFHGDEEIIEVVELDPGPPDP... MACWPQLRLLLWKNLTFRRRQTCQLLLEVAWPLFIFLILI.

13 Known drug targets matched to interacting compounds MGKNKLLHPSLVLLLLVLLPTDASVSGKPQYMVLVPSLLH... MESESESGAAADTPPLETLSFHGDEEIIEVVELDPGPPDP... MACWPQLRLLLWKNLTFRRRQTCQLLLEVAWPLFIFLILI... MGFVRQIQLLLWKNWTLRKRQKIRFVVELVWPLSLFLVLI... none MLEICLKLVGCKSKKGLSSSSSCYLEEALQRPVASDFEPQ protein-based queries compound-based queries homologs in parasites protein features expression profiles polymorphisms RNAi/ko validation evidence similar compounds properties (e.g., Lipinski) correlation with toxicity development status feasibility cost of goods

14 Integration of parallel target initiatives à TDR Targets Database Distribution of data for community access & annotation

15 Research may have 1-2 overall goals:" adapted from Stokes, D.E. Pasteur s Quadrant. Basic Science and Technological Innovation. Brookings Institutional Press, Potential New Use? Yes No Potential New Understanding? Yes Louis Pasteur Niels Bohr No Thomas Edison?? but, classroom labs usually address neither aim (beyond the student) one of my teaching goals is to use real-world relevant research assignments as much as possible.

16 Expansion of the data set

17 Whole genome drug target assessment

18 What proportion of known drug targets have homologs in pathogen genomes? Parasite (gene number) Ortholog Matches additional Homolog Matches additional Domain Matches Total DrugBank Matches T. brucei 151 (12%) (36%) T. cruzi 175 (14%) (39%) L. infantum 166 (13%) (36%) L. major 173 (14%) (38%) P. falciparum 123 (10%) (31%) HIV (0.2%) Known Target Space (DrugBank = 1279 targets)

19 What proportion of drug targets have homologs in all kinetoplastid parasites? Parasite (gene number) Ortholog Match Homolog Match Domain Match Total DrugBank Matches T. brucei 151 (12%) (36%) T. cruzi 175 (14%) (39%) L. infantum 166 (13%) (36%) L. major 173 (14%) (38%) Kinetoplastida a 33 b 395 Matching targets approved drugs Matching targets experimental compounds a - 63 of 252 are orthologs to 1, 2, or 3 genomes, the other 189 are homologs only b - 22 of 33 are orthologs or homologs to 1, 2, or 3 genomes, the other 11 are domain matches only

20 Noise vs Signal?

21 Prediction of BBB penetration (T. brucei targets with BBB crossing compounds) 462 Drug Discovery Targets with DrugBank compounds 250 have chemical structures in ACD/CMC/MDDR databases 60 chemicals pass our criteria... a) Lipinski filter (N+O 10, MW 500, H donors 5, AlogP 5) b) Polar Surface Area filter (N+O+P+S<70Å 2 ) c) manual curation to remove metabolites >15 targets with compounds predicted to cross BBB to be able to reach CNS infections

22 PDEs have RNAi validation in trypanosomes and have been popular targets for chemistry work in many companies

23 Two new paths overcome potency ceiling Broaden screen x10,000 Recently awarded project at Tres Cantos Open Lab Foundation - Will screen GSK collection - Parasite screen followed by PDE biochemical screen - HTS assay to replace our low throughput coupled enzyme assay Obtain PDE-compound structure(s) PDEB crystallography collaboration: - Nick Bland working at Brown with Rebecca Page and Wolfgang Peti

24 Lessons and Opportunities Lessons learned for drug repositioning - Many prediction methods but few successes What are we missing?! - Lack of data sets to assess and validate predictors Opportunities - Correlation of compound activity with target concentration and pathway/network dynamic activity in screens - Still lack a suitable database to facilitate omics queries exploiting the >1M compounds annotated for activity in ChEMBL, PubChem, and other DBs (and lack a mechanism to facilitate tool compound validation and access) - Neglected disease pipelines are still weak and sharing of data and compounds is still to slow (tension between sharing data and not getting scooped especially in tough funding times)

United States House of Representatives. I am the Executive Director of the North America office

United States House of Representatives. I am the Executive Director of the North America office Rachel M. Cohen, Executive Director Drugs for Neglected Diseases initiative, North America Written Testimony, Outside Witness Hearing Subcommittee on State and Foreign Operations, Committee on Appropriations