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2 lead compounds identified from 2 novel chemical series:- AW 464 (1 st series)

2 lead compounds identified from 2 novel chemical series:- AW 464 (1 st series) AJM 290 (2 nd series) Potent, selective in vitro and in vivo activity: renal, colon, breast, melanoma cell lines Evidence suggests activity associated with inhibition of HIF signalling

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2 lead compounds identified from 2 novel chemical series:- AW 464 (1 st series)

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  1. 2 lead compounds identified from 2 novel chemical series:- AW 464 (1st series) AJM 290 (2nd series) Potent, selective in vitro and in vivo activity: renal, colon, breast, melanoma cell lines Evidence suggests activity associated with inhibition of HIF signalling Preclinical development underway – selection of clinical development candidate by mid-2005 Current status

  2. Lead candidates AW 464 and AJM 290 Potent in vitro activity Renal, colon, breast and melanoma cell lines AW 464 GI50≤ 300nM AJM 290GI50≤ 10nM Cisplatin-resistant cell lines (GI5070 - 216µM) AW 464 GI50≤ 1.6µM AJM 290 GI50≤ 100nM MTX-resistant colon lines (GI50 > 100 μM cf < 100 nM wt) AW 464 GI50 < 400 nM AJM 290 GI50 < 300 nM Significant in vivo activity AW 464 i.p. renal hypernephroma AJM 290 i.p. colon, renal and melanoma xenografts AJM 290 orally active in colon and melanoma xenografts Quinol program

  3. Discovery • novel structures via oxidation of interesting phenols • rigorous antitumour profiling of resulting new chemical entities

  4. AW 464 – synthetic accessibility Wells et al. J. Med. Chem. 2003, 46, 532-541

  5. AJM 290 – synthetic accessibility Berry et al. J. Med. Chem. 2005, 48, 639-644

  6. In vitro antitumour activity NCI mean LC50 graphs: AW 464AJM 290 Colon Melanoma Renal Renal Wells et al J Med Chem 46 532-541, 2003

  7. AW 464 -Mechanism(s) of Action: • Inhibition of Thioredoxin signalling – dose dependent Up-regulation of TR gene expression in HCT 116 cells: 1 μM; 10 μM AW 464 (24 h) Inhibition of Trx/TR-catalysed insulin reduction

  8. AW 464 -Mechanism(s) of Action: • Inhibition of HIF signal transduction - dose-dependent inhibition VEGF production under hypoxia and normoxia - dose-dependent down regulation of CA-IX protein - dose-dependent down regulation of BNIP3 protein • Anti-angiogenic activity -dose-dependent inhibition VEGF production - Inhibition of human umbilical cord vein endothelial cell proliferation (IC50 0.5 μM) - Inhibition of endothelial cell differentiation (tubal abortion 0.5 μM, matrigel model)

  9. Cell Number H2DCFDA fluorescence DMSO AW 464 24 h AW 464 -Mechanism(s) of Action: • Perturbation of REDOX regulation • Generation of reactive oxygen species (ROS) 3 – 6 h • Induction of apoptosis 12 – 16 h • Dose-dependent CDK-1 downregulation • G2/M block, preG1 population • Breast and colon cell lines

  10. AJM 290 -Mechanism(s) of Action: • Inhibition of HIF signal transduction -dose-dependent inhibition VEGF production under hypoxia and normoxia (antiangiogenic activity) - dose-dependent down regulation of CA-IX protein - dose-dependent down regulation of BNIP3 protein • Direct inhibition of thioredoxin unconfirmed Gene array did not show enhanced TrxR transcription in cells treated with AJM 290 (0.5 μM, 24 h)

  11. AJM 290 -Mechanism(s) of Action: • Generation of ROS (HCT116, 3h, 0.5 μM AJM 290) • Emergence of apoptotic population(HCT116, 7–16 h, 0.5 μM AJM 290) • Dose-dependent down regulation of CDK-1, G2/M cell cycle block and appearance of pre G1 peak.

  12. AW 464 in vivo antitumour activity • AW 464causessignificant growth inhibition in the highly angiogenic renal hypernephroma xenograft RXF 944XL model: NSC 706704 = AW 464 15 mg/kg delivered i.p. A) days 1 and 8 B) days 1 and 2

  13. AJM 290 in vivo antitumour activity • Significant activity in 3/3 xenograft models – colon, melanoma, renal route: i.p. dose: HCT 116, MDA-MB-435 CAKI-1 150 / 200 mg/kg d 7 100 / 150 mg/kg d 7, 14 25 / 50 mg/kg d 7-11 25 / 50 mg/kg d 7-11

  14. day AJM 290 in vivo antitumour activity • Melanoma (MDA-MB-435) xenografts • Route p.o - Dose d 12-16 • Solvent vehicle: saline containing 10% DMSO + 0.05% Tween 80

  15. day AJM 290 in vivo antitumour activity • Colon (HCT 116) xenografts • Route p.o - Dose d 12-16 • Solvent vehicle: saline containing 10% DMSO + 0.05% Tween 80

  16. Lead Candidate Selection: AJM290 vs AW464 In vivo efficacy– includes testing via oral route of administration Selectivity against receptors with pharmacological / safety implications 50 receptors (Cerep ExpresProfile) AJM290- No significant interaction AW464 – Antagonist activity against hH-1 receptor (IC50 3µM) Metabolic liability Inhibition of key drug metabolising enzymes (CYPs 3A4, 1A2, 2D6, 2C9 and 2C19) No significant inhibition with either compound Metabolic stability – to be determined Pharmacokinetics– ongoing Pharmaceutical properties- ongoing

  17. Preclinical Development Timelines Candidate nomination Sep 05 Pharmacology / Toxicology Jun 06 CMC: Formulation Development / Manufacturing Sep 06 Clinical Protocol Sep 06 IMPD or IND Oct 06

  18. The multiple intracellular roles of Thioredoxin

  19. Model of AW 464 bound to human thioredoxin

  20. AW 464 binding to Thioredoxin active site

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