DHODH: StructureGuided Design of a. New Class of Drugs. Defeating Malaria Together. Meg Phillips, Ph.D. UT Southwestern

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1 DHODH: StructureGuided Design of a New Class of Drugs Defeating Malaria Together Meg Phillips, Ph.D. UT Southwestern 1

2 Pipeline to development of a DHODH-based anti-malarial 2001 Phillips enzymology/ structure/hts; Rathod parasitology, med chem Target 2004 NIH funding Phillips/Rathod Program: Brewer/ Rogers HTS Screen Actual or potential inhibitors Validated hits 2006 Charman: ADME DSM team 2007 MMV/NIH funding to Phillips/Rathod/Charman Animal models Advisors: Bathurst, Burrows, Floyd, Matthews, Craft, Dayan Leads 2009 Coteron/GSK GSK, Buckner Safety Pharmacology 2009: 3 DHODH teams - DSM/GSK/ Genzyme Drug Candidate Preclinical and Clinical development Iterative medicinal chemistry Drug Optimize efficacy and pharmaceutical properties Global Academic and Industrial Inform with X-ray Structure Partnership facilitated by MMV and NIH virtual drug company

3 Identifying a target - pinpointing vulnerable biology in the cell Nucleus Chromosome DNA Base pairs Bases (nucleotides) are the building blocks of DNA

4 How Parasites Replicate their Genetic Material U Host Salvage G A Synthesis UMP T C Building blocks for DNA and RNA Host and Malaria Parasite X An essential pathway X CO 2 + amino acids 4

5 DHODH the target of a novel potential therapy CO 2 + amino acids Human DHODH DHODH DHO Drug binding site orotate U G T A C Building blocks for DNA and RNA DNA and RNA Malaria DHODH Differences in the shape of the drug binding site Parasite enzyme can be selectively blocked

6 Identifying malaria parasite selective DHODH inhibitors Start with 200,000 drug like chemicals find the needle in the haystack 6

7 High throughput screen (HTS) to identify DHODH inhibitors UT Southwestern screening core Phillips lab Blue to white screen Inhibitor = blue Plate potential inhibitors on 384 well plates (520) and assay enzyme Identified 1350 compounds that inhibited malaria DHODH Baldwin, et al J. Biol. Chem. 2005, 280,

8 Triazolopyrimidines - The Lead Compound Series HTS identified potent and selective inhibitors of P. falciparum DHODH ~12 structural classes; 60 compounds with IC 50 < 500 nm Lead series triazolopyrimidines PfDHODH ( IC 50 = 50 nm); human DHODH (>200,000 nm) Typical drug 5 10 nm Fraction active >200,000 nm Phillips, et al J. Med. Chem. 2008, 51,

9 Mechanism of parasite killing by DSM1 %parasite survival >6,000 nm Malaria DHODH Pyrimidine biosynthesis Parasites grow die DSM1 potent inhibitor of parasite growth in vitro Painter, et al Nature 2007, 446, University of Washington Rathod lab

10 Mechanism of parasite killing by DSM1 University of Washington Rathod lab %parasite survival Malaria DHODH Yeast DHODH DSM1 Pyrimidine biosynthesis DSM1 potent inhibitor of parasite growth in vitro DHODH is primary target of cell killing Identified a potent DHODH inhibitor, but not effective in animals Next step understand metabolism and plasma exposure Parasites grow

11 Identifying compounds that kill parasites in animals and man DSM1 Chemistry: University of Washington Rathod lab DSM74 ADME: Monash University Charman lab Library of ~80 analogs with naphthyl replacements synthesized Identified compounds that show good stability Gujjar, et al J Med Chem Apr 9;52(7): ; Gujjar, R., et al. (2011) J. Med. Chem., in press.

12 Malaria parasite growth inhibited in P. berghei mouse model PfDHODH 270 nm hdhodh > 100,000 nm Pfalcip 3D7 320 nm Oral dosing First proof of concept that DHODH inhibitors can suppress parasites in vivo No evidence of toxicity Compound lacks potency required of clinical candidate Another round of lead optimization University of Washington Buckner/Rathod lab Gujjar, et al J Med Chem Apr 9;52(7):

13 X-ray structure provided insight to improve potency R 1 R N N N HN N R1 = CF 3, SF 5 or Cl R = CF 2 CH 3, CF 3, OCH 2 CH 3, CH 2 CH 3 and many others UT Southwestern Med Center Phillips lab GSK Tres Cantos Coteron lab A library of 100 molecules were synthesized to find the optimal R-group

14 X-ray structure provided insight to improve potency In vitro P. falciparum assay Improved potency fold for redesigned molecules (DSMRD) PfDHODH and whole cell activity meet development criteria Metabolism and plasma exposure? WO 2011/041304; PCT/US2010/050532, 4/07/11, 2011

15 Candidates pharmacokinetic profile in rats Good oral bioavailability Prolonged plasma exposure Long half-life supports meeting Target Product Profile of once daily dosing Identified a potent compound with good plasma exposure, what about in vivo activity? Monash University Charman lab 15

16 Candidate mouse efficacy study SCID mouse Single oral dose per day for 4 days As potent as Chloroquine (ED 50 = 3.2 mg/kg) works on drug resistant parasites Candidate meets development criteria for efficacy GSK Tres Cantos - Iñigo Angulo Barturen and Santiago B. Ferrer

17 Pipeline to development of a DHODH-based anti-malarial Target HTS Screen Actual or potential inhibitors Validated hits Animal models Leads Iterative medicinal chemistry Ames negative CEREP panel clean Rabbit Ventricular Wedge assay clean Optimize efficacy and pharmaceutical properties Inform with X-ray Structure Animal Tox - ongoing Safety Pharmacology Summer 2011 Drug Candidate Drug Preclinical and Clinical development Pink, et al Nature reviews drug discovery (2005) 4,

18 The Team a global partnership UT Southwestern Meg Phillips, Ph.D. Farah El_Mazouni Xiaoyi Deng Nick Malmquist Betsy Goldsmith Jeff Baldwin University of Washington Pradip Rathod, Ph.D. Ramesh Gujjar John White Rapat Patrapuvich Jenny Gϋler Fred Buckner Sharon Creason Monash University Sue Charman, Ph.D. Bill Charman, Ph.D. Karen White David Shackleford Akhil Vaidya GSK Spain Med chem support: Jose Coteron, Ph.D. María Marco-Martín and Jorge Esquivias-Provencio, chemists SCID Mouse models: Iñigo Angulo Barturen and Santiago B. Ferrer Genzyme Ted Sybretz and Jeff Klinger Advisors: Ian Bathurst (MMV), Jeremy Burrows (MMV), John Rogers (NIH), Dave Matthews, David Floyd, Carl Craft Funding: NIH U01AI075594; Medicines for Malaria Venture