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VC presentation. Pharminox Drug Discovery Platform. The Big Pharma Cancer Drug Discovery Paradigm. Genomics (< 25,000 genes in H. sapiens genome). Proteomics (identification of proteins relevant to cancer initiation and development). Target identification and validation. Molecule hunt

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  1. VC presentation Pharminox Drug Discovery Platform

  2. The Big Pharma Cancer Drug Discovery Paradigm Genomics (< 25,000 genes in H. sapiens genome) Proteomics (identification of proteins relevant to cancer initiation and development) Target identification and validation Molecule hunt (to identify ‘hits’ then ‘leads’) Lead optimisation Clinical candidate

  3. “Until proven effective in the clinica novel target is just a target wannabe” Tito Fojo, The Oncologist, 2001, 6, 313-314

  4. The Pharminox Drug Discovery Platform • Synthesisof molecules with novel pharmacophores • Screeningof molecules in intact cellular systems • Identificationof molecules which produce unique phenotypic responses • Target identification by developmental • pharmacology (eg gene arrays, proteomics), and • integrated medicinal and computational chemistry • Selectionof an elegant pharmaceutical for clinical trial See: Drug Discovery Today, 2004, 9, 625-627

  5. In vitro profile of 5F 203 in the NCI 60 cell panel Mean GI50 graph 5F 203

  6. Six compounds into clinical trial: NMF, Bropirimine, MZPES, Mitozolomide, Temozolomide, Phortress • Two series of compounds in pre-clinical development: Quinols, Telomerase inhibitors Record of the Cancer Research UK Experimental Cancer Chemotherapy Research Group (1980-2004) • Two compounds on the market: Temozolomide (world-wide), Bropirimine (Japan) • <100 molecules/project and <£10 million total research expenditure(1980-2005) from CRC/CR UK

  7. Search for a second-generation temozolomide Program goal • To synthesise and develop potent novel analogs of temozolomide with broad-spectrum activity against temozolomide-resistant tumors Program status • Concept development • Preliminary investigative chemistry

  8. Chemical Whispering: The Stone-Stevens Synthesis of Temozolomide Robert Stone PhD Student, Aston University, Birmingham UK, 1978-1981 J. Med. Chem., 1984, 27, 196-201

  9. Temozolomide: the competition • Canadian compounds • Amsterdam compounds • UK compounds Temozolomide prodrugs funded by Cancer Research UK (structures unknown)

  10. Temozolomide targets especially brain tumours with a silenced O6-alkyl-DNA alkyltransferase (MGMT) repair gene Background • Temozolomide alkylates DNA at the O6-position • of guanine residues in GGG rich sequences

  11. Program Objectives (1) • Development of analogs with enhanced potency and which form a non-repairable DNA lesion

  12. Program Objectives (2) • Analogs bioactivated within hypoxic tumor masses

  13. Program Objectives (3) • Analogs with reversible linkages to DNA repair inhibitors

  14. Molecular combination of an imidazotetrazine and an O6–alkylguanine-DNA alkyltransferase (MGMT) inhibitor.

  15. Molecular combination of an imidazotetrazine and a PARP-1 inhibitor

  16. Background The methylation status (at cytosine C-5) of the MGMT gene promoter correlates with survival in glioblastoma patients treated with temozolomide Clin. Cancer Res., 2004 Program goal To develop a novel agent capable of methylating cytosine residues in CpG sequences of gene promoters Towards a molecule to methylate cytosine residues of DNA at C-5

  17. The strategy: To develop a small molecule construct which could mimic the chemistry of the enzyme cytosine 5-methyltransferase

  18. The telomerase project: starting point Lactarius necator

  19. Duplex telomeric repeats in t-loop 3´ G-strand overhang in D loop Possibilities of telomerase inhibition for therapeutic intervention ? ? Reversetranscriptase inhibitors ? ? TP1 hsp90 dykserin Tankyrase MRE11 RAD50 TERT TIN2 Ku TRF1 TRF2 hTR -TTAGGGTTAGGGTTAGGGTTAGGGTTAGGGTTAG -AATCCCAATCCC RNA template (antisense) G - quadruplex stabilization

  20. Molecular modelling of RHPS4 G-quadruplex interaction 10 3 6 My thanks to Charles Laughton and Chris Grindon

  21. Selecting a Clinical Candidate RHPS3 RHPS4 IH383 RHPS16

  22. Ease of synthesis – two routes Selective stabiliser of G-quadruplex DNA Potent inhibitor of telomerase (IC50 0.33 mM) Rapid inducer of senescence Induces telomere shortening Soluble in water (> 5 mg/mL) Resistant to metabolism by CYPs Rapidly accesses nuclei of cells Potent in vitro and in vivo antitumour activity Potential broad spectrum agent Dossier for clinical trials being prepared (CR UK) Summary of status of RHPS4

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