ALM301: Allosteric Isoform selective Akt inhibitor

Transcription

1 ALM301: Allosteric Isoform selective Akt inhibitor

2 Background Akt1/2 selective inhibitors ALM301 Back-up compounds Akt2 selective inhibitors

3 Approaches to Akt Inhibition Both ATP competitive and allosteric inhibition approaches are reported Phenotypical response is not the same ATP competitive inhibitors Many described, several in Phase I, one in Phase II Results in hyper-activation of Akt pathway (Okuzumi et al ) Selectivity difficult to achieve against AGC kinase family members Allosteric inhibitors Act through interaction with the PH domain, stabilising the inactive enzyme and preventing phosphorylation by mtorc2/pdk1 In contrast to ATP competitive inhibition, the Akt pathway is down regulated through allosteric inhibition (Barnett et al ; Calleja et al ) MK-2206, pan Akt inhibitor with biochemical potency in range nM currently in multiple clinical trials Almac Discovery s programme aims to identify isozyme selective PH domain dependent Akt inhibitiors 1 Nat Chem Biol 5, ; 2 Biochem J 385; ; 3 PloS Biol 7; e17

4 Protein Expression of Akt Isoforms in Tumour Tissue Microarrays Berglund et al (2008) Mol Cell Proteomics (10): Akt1 Akt3 Akt2 Cancer tissues frequently show increased expression of Akt1 and/or Akt2 isoforms Few cancers show increased activation of Akt3 Inhibitors used clinically have a pan Akt isoform profile Akt1/2 inhibition expected to be sufficient to treat the majority of cancers

5 Synergy Profile of Akt1/2 Selective Inhibitor In many cases hyper-activation of Akt is correlated with drug resistance MEK inhibitors (Roth et al 2009) Notch inhibitors (Ferrando et al 2008) Cisplatin (Tsang et al 2009) Taxols (Varbiro et al 2009) EGFR inhibitors (Hirai et al 2010) Synergy between ALM301 and a range of chemotherapeutics has been established in LnCaP cells includes: Lapatinib, Vorinostat, Doxorubicin, Gefitinib, AZD6244 Strong synergy also demonstrated in A2780, A549, MCF- 7 and PC3 cell lines Synergy with radiation has been demonstrated with an Akt1/2 selective inhibitor

6 Biological potency of ALM301 Biochemical potency >10 fold selective for Akt1 & Akt2 over Akt3 Inhibition is PH domain dependent No off-target inhibition 10μM in panel of 50 kinases Cellular potency ELISA pakt IC 50 in range nM across a range of cancer cell lines Greater anti-proliferative effect in cancer cell lines versus normal cell lines 60 IC50 (µm) MCF7 A2780 H460 HCT116 LNCAP A431 T47D PC3 PANC-1 A549 HT29 SKOV3 PNT2 Proliferation IC50s across a panel of cancer (black) and normal (red) cell lines DU145 U251MG HMEC-1 HFFF2 InMyoFib NHLF Hs888Lu FR2 HELA MDA-231 SW480

7 In vitro/in vivo ADME Good stability in microsomes and hepatocytes across species (human, mouse, rat, dog) PPB% in range 50-85% across species Clearance in rat and dog <50% liver blood flow Oral bioavailability in rat and dog > 40% Based on in vitro-in vivo modelling, expect a human T1/2 in line with q.d. dosing

8 In vitro Selectivity and Toxicity Profile ALM301 herg IC50 ( M) >10 CYP Inhibition IC50<25 M all >25 M (3A4, 2D6, 1A2, 2C9, 2C19) CYP Time dependent inhibition (3A4, 2D6, 1A2, 2C9, 2C19) IC50 shift>1.5 no shift for any isoform Selectscreen Kinase Panel Kinases 10 M Akt1 (% inhibition, 50 kinases) Genotoxicity panel Ames/micronucleus negative No significant off-target toxicity risk identified

9 In Vivo Efficacy Studies Study Designs: MCF-7 Single agent ALM301 p.o. (3,10, 30mg/kg q.d. 100mg/kg q.o.d.) Single agent Tamoxifen (5 mg/kg q.d.) Combination ALM301 p.o (3,10mg/kg q.d., 100mg/kg q.o.d.) + Tamoxifen (5 mg/kg q.d.) LnCaP Single agent ALM301 p.o. (30mg/kg q.o.d.) Single agent Bicalutamide i.p. (8mg/kg q.d.) Combination ALM301 (30mg/kg q.o.d.) + Bicalutamide (8mg/kg q.d.) Tumour volumes and body weights measured Mouse xenograft studies also carried out in lung and glioma models

10 ALM301 inhibits MCF-7 tumour growth Group 1 -Vehicle ALM301 3mg/kg p.o. q.d. T/C Tumour volume (mm 3 ) ALM301 10mg/kg p.o. q.d. ALM301 30mg/kg p.o. q.d. ALM mg/kg p.o. q.o.d. * * p< Day from treatment start Tumour stabilisation at 30mg/kg, regression at 100mg/kg

11 Tumour regression when combined with Tamoxifen 600 Vehicle Tamoxifen 5mg/kg ALM301 3mg/kg q.d. + Tamoxifen 5mg/kg ALM301 10mg/kg q.d. + Tamoxifen 5mg/kg ALM mg/kg q.o.d. + Tamoxifen 5mg/kg T/C Tumour volume (mm 3 ) * p= Day from treatment start Significant synergy observed with Tamoxifen at 100mg/kg

12 Mean body weight loss <10% across all groups Body weight (% of Day 1) Vehicle ALM301 3mg/kg q.d. ALM301 10mg/kg q.d. ALM301 30mg/kg q.d. ALM mg/kg q.o.d. Tamoxifen 5mg/kg Tamoxifen 5mg/kg + 3mg/kg ALM301 q.d. Tamoxifen 5mg/kg + 10mg/kg ALM301 q.d. Tamoxifen 5mg/kg + 100mg/kg ALM301 q.o.d Day from treatment start

13 Back Ups Advanced back-up compounds from a different chemical series, with either similar or different selectivity profiles, are available if issues with ALM301 are identified

14 Path to the clinic Significant collaboration with the Sanger Institute to screen Almac Discovery Akt inhibitors across hundreds of cancer cell lines Almac Discovery Akt inhibitors shown to be active in PIK3CA mutant cancer cell lines from specific tissues Aim to identify patient cohorts with PIK3CA mutations in specific tumour types

15 Intellectual Property ALM301 is a specific example in one of the following patents: WO WO WO

16 Why Almac Discovery for allosteric Akt inhibitors? Almac Discovery has a portfolio of allosteric inhibitors selective for one or more isoforms of Akt ALM301 nominated as the preclinical candidate ALM301 is differentiated from ATP competitive inhibitors by: Akt1/2 isoform selectivity, plus excellent selectivity against other kinases Differential effect on Akt pathway (downregulation vs hyper-activation) Back up compounds available Different chemical series from ALM301 Very good potency, ADMET and PK properties

17 Please contact: Robert Grundy PhD Director of Commercial Development and Licensing Tel: + 44 (0) robert.grundy@almacgroup.com