Potent HCV Antiviral Activity by Inhibiting Fatty November 11, - - PowerPoint PPT Presentation

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Potent HCV Antiviral Activity by Inhibiting Fatty November 11, - - PowerPoint PPT Presentation

Jan 17, 2023 251 likes •377 views

Potent HCV Antiviral Activity by Inhibiting Fatty November 11, Acid Synthase 2012 AASLD George Kemble, PhD CSO Drug Profile: Rationale & Approach Unique mechanism of action to enable the following: Pan genotype

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SLIDE 1

Potent HCV Antiviral Activity by Inhibiting Fatty Acid Synthase
 


George Kemble, PhD
 CSO

November 11, 2012 AASLD

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SLIDE 2

Drug Profile: Rationale & Approach

  • Unique mechanism of action to enable the following:

– Pan genotype antiviral activity – Activity against other classes of drug resistant HCV mutants – Well tolerated – High barrier to resistance

  • Approach

– Identify a cellular protein that is:

  • required for HCV replication
  • not critical for day to day function of the host

– Develop proprietary compounds that fit with the evolving SOC

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SLIDE 3

Fatty Acid Synthase (FASN)

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Acetyl-CoA + 7 Malonyl-CoA + ATP, NADPH Maier, et al. Science, 2002 PDB ID: 2CF2 Chakravarthy, et al, Cell Metabolism, 2005

Palmitate

Post- translational modifications (eg NS4b) Other fatty
 acids & complex lipids Diglycerides & Triglycerides

FASN

Adult mice lacking liver FASN are normal

  • Large, homodimer
  • Multiple enzymatic domains
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SLIDE 4

HCV Depends on the FASN Pathway


 
 
 
 
 
 
 
 


Virus Assembly and Exit RNA Replication Viral Entry

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FASN and/or its product interact with HCV at 
 multiple points of the viral replication cycle

Yang, et al, Hepatol. (2008)

Yu, et al, J. Virol (2006)

Sakamoto, et al. Nat. Chem Biol (2005) Umehara, et al., Biochem & Biophys Res. Comm (2006)

Majeau, et al, J. Biol. Chem (2009) Moradpour et al. Nature Reviews Microbiology (2007)

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SLIDE 5

3-V Inhibitors Are Potent & Specific

Inhibitory (50%) Concentration FASN Enzyme in vitro FASN Enzyme in cells GT1b Replicon* GT2a Virus* 50 nM 40 nM 60 nM 41 nM

*No toxicity observed at highest concentration tested (10,000 nM) 5

GT1b Replicon Infectious HCV (Gt2a)

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SLIDE 6

FASN Inhibition Blocks HCV RNA Replication & Protein Expression

0.0 20.0 40.0 60.0 80.0 100.0 48 72 96

Inhibition of HCV RNA Replication No Drug NS5a Ab

% Luciferase Inhibition

3-V FASN Inhibitor Treatment (hrs)

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SLIDE 7

FASN Inhibition Reduces HCV RNA In Passaged Cell Lines

25 50 75 100 5 10 15 20 25 % HCV RNA Relative to 
 Untreated Cells 
 (normalized to GAPHD) Days Post Treatment No Drug

  • Prot. Inhib

3-V FASN Inhib

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SLIDE 8

Targeted Inhibition of FASN


Palmitate add-back demonstrates on-target mechanism

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10- 5 10- 4 10- 3 10- 2 10- 1 100 101 102 0.0 0.5 1.0 1.5

TVB-0002722 TVB-0002722 + PA 10uM TVB-0002722 + PA 25uM TVB-0002722 + PA 50uM

Concentration, uM de novo PMT Response

FASN inhibitor + / - Palmitate HCV RNA replication (Luciferase) FASN enzymatic activity (palmitate synthesis)

HCV Replicon

HCV RNA repl is restored FASN is inhibited

de novo palmitate
 synthesis (response)

3-V inhib. 3-V inhib. + 10µM palmitate 3-V inhib. + 25µM palmitate 3-V inhib. + 50µM palmitate 3-V inhib. 3-V inhib.+ 10µM palmitate 3-V inhib. + 25µM palmitate 3-V inhib. + 50µM palmitate

Concentration, µM Concentration, µM

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SLIDE 9

3-V FASN inhibitors active against a range of HCV variants

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Median Efgectiveness Concentration (µM) Gt1a Gt1b Gt2 0.06 0.06 0.10 Active across genotypes Active against replicons
 resistant to other classes 


  • f HCV drugs

30 60 90 120 % Activity Compared
 to WT replicon

Drug Resistant 
 Mutation in Gt1b Replicon

3-V inhibitor Control Cmpds (DAAs)

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SLIDE 10

FASN inhibited in rats following oral administration

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12 or 24 hours

3-V FASN inhibitor Oral gavage (t=0) Add

13C Acetate

Tracer (t=10 or 22 hrs)

Harvest Liver Analyze 13C Palmitate

25 50 75 100 125 150 30 mpk 60 mpk 30 mpk 60 mpk Veh Veh 12 hr post dose 24 hr post dose

% FASN Activity

* *

P<0.05 Mann-Whitney

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SLIDE 11

Profile of 3-V’s FASN inhibitors

  • Attractive compounds with unique mechanism of action

– On-target activity confirmed – Potent (EC50’s < 100nM) – Pan genotype antiviral activity – Active against HCV mutants resistant to various classes of DAAs – Well tolerated following multiple day dosing at levels that
 suppress liver FASN in rats

  • IND

enabling studies underway

  • Phase 1 and proof of concept in HCV patients in 2013

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SLIDE 12

3-V Biosciences, Inc. Contributors


Doug Buckley
 Marc Evanchik
 Robert McDowell
 Stefan Moese
 Yamini Ohol
 Johan D. Oslob
 Merdad Parsey
 Amy K. Patick
 Mohan Sivaraja
 Sam Tep
 Satya Yendluri
 
 Visit Poster #1876 for additional information