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Cathepsin K as a target for Osteoporosis

Team 6

https://www.ebi.ac.uk/pdbe/entry/search/index?uniprot_accession:(P55097%20OR%20P43235)

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Roadmap

  1. Disease Overview and Current Therapies

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  • Cathepsin K and Target Validation

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  • Project Flow Chart

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  • SWOT Analysis

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  • Conclusion

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Bone Remodeling

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https://www.marahnaturalusa.com/sac-osteoporosis

Osteoclasts are bone cells that break down bone tissues.

Osteoblasts are bone cells that synthesize bone tissues.

The imbalance between bone resorption and bone formation causes osteoporosis.

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Description of Osteoporosis

  • Osteoporosis is a bone disease that occurs when the body loses too much bone, makes too little bone or both, resulting in an increased risk of broken bones

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  • Osteoporosis is mainly caused by a lack of certain hormones such as estrogen and androgen in women and men respectively.

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Source: https://en.wikipedia.org/wiki/Osteoporosis

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�Treatment of Osteoporosis

Anabolic therapy

    • Diet calcium and vitamin D
    • Hormone replacement therapy (HRT)
      • Teriparatide (Forteo)

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Bone resorption inhibitors:

  • Bisphosphonates are the most common medications
                  • Alendronate (Fosamax)
                  • Risedronate (Actonel)
                  • Ibandronate (Boniva)
                  • Zoledronic acid(Zometa)

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Potential Mechanism of Treatment

http://slideplayer.com/slide/10594917/

Targets Osteoblast

  • Teriparatide, PTH analog
  • Estrogen therapy SERM, Hormones

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Targets osteoclast

  • Denosumab
  • Bisphosphonates
  • Cathepsin K inhibitor

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What is Cathepsin K?

http://www.nature.com/bonekey/knowledgeenvironment/2008/0801/bonekey20080294/fig_tab/bonekey20080294_F1.html

Mechanism Includes:

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  • Osteoclast attaches to bone (via αVβ3 integrin)

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  • Acidic environment between cell and bone forms, prompting release of Cathepsin K from lysosomes

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  • Increase bone degradation and bone resorption occurs

A Lysosomal Protease Involved in Bone Resorption

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Cathepsin K as a Target

  • One of several enzymes in the cysteine protease family

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  • Unique Quality: triple helical collagen unfolding which causes it to play the largest role in bone resorption process

→ Prime target for halting resorption and treating Osteoporosis.

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https://www.researchgate.net/figure/The-three-dimensional-structure-of-cathepsin-K-The-three-dimensional-structure-of-human_fig2_236581058

http://www.pnas.org/content/111/49/17474.full

Triple helix of collagen being unwound by CatK

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Published Data on Cathepsin K Inhibition

  1. Novartis - Balicatib:
  2. anti-resorption + bone formation

2) GlaxoSK - Relacatib:

  • Waiting on published data

3) Merck - Odanacatib:

  • decreased resorption + bone density
  • Phase III (Stroke Risk + low enrollment)

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*No Cathepsin K Inhibitors currently on the market

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Project Flow Chart

Stage

1

2

3

In vitro biochemical, human and murine

Liver microsome assay

Rabbit, in vivo

In vitro cell, murine

Rodent, PK

4

5

In vitro cell, human

CatK inhibition, selectivity, compound stability

CatK inhibition

CatK inhibition, increase bone mass

Monkey, in vivo

CatK inhibition, increase bone mass, resorption pit size

Half-life, bioavailability,

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Assays for in vitro

Use of human progenitor cells

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  1. Stained for

Cathepsin K

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B) Unchanged

osteoclasts

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C)Increased bone

resorption with increased

doses The effects of the cathepsin K inhibitor odanacatib on osteoclastic bone resorption and vesicular trafficking

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Assays for in vivo

Estrogen deficiency in skeletally mature rabbits

  • increased bone mass
  • reduced urinary helical peptide of collagen type 1 (bone resorption biomarker)
  • maintained bone specific alkaline phosphotase (BSAP-bone formation marker)

Ovariectomized rhesus monkey

  • similar criteria

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Assays for Target Selectivity

-Minimize binding to other cysteine cathepsin groups (L,S and V being most similar to K)

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-Measurement of tissue levels of mice administered with Cathepsin K inhibitors.

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-Aided by the use of in-silico screening.

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Strengths and Weaknesses

Strengths

Weakness

  • Novel Approach: Does not affect bone formation
  • Validated Target
  • Many tested structures available as reference
  • Fully annotated CTSK gene available
  • Selectivity: location(osteoclast) and protease type (L, S & V are similar to K): major cause of PhIII trial failure
  • Also found highly expressed in breast cancer
  • Broad exp. in gall bladder

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Threats and Opportunities

Opportunities

Threats

  • Medical needs exist among special populations
  • Increasing # of Osteoporosis patients WW
  • Would be first of kind
  • Parallel/joint study might be possible for other therapies, i.e. breast cancer (possible new indication)
  • New approaches for osteoporosis therapy (future therapy paradigm change)
  • Merck and other competitors (value vs. risk)

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Conclusion

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  • New approach (would be the first cathepsin K inhibitor in the market)
  • Increasing population in the future
  • Once successful=> has long term market access
  • Competitors (Rx & generics)

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  • Selectivity

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References

  1. Science. (2000). Steven L. Teitelbaum, et al. Bone Resorption by Osteoclasts. Available at: http://science.sciencemag.org/content/289/5484/1504.full
  2. Wiley Online Library. (2001). Mone Zaidi, et al. Cathepsin K, Osteoclastic Resorption, and Osteoporosis Therapy. Available at: http://onlinelibrary.wiley.com/doi/10.1359/jbmr.2001.16.10.1747/full
  3. NCBI. (2014). Adeleke H. Aguda, et al. Structural basis of collagen fiber degradation by cathepsin K. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267343/
  4. NCBI. (2009). Dieter Bromme, et al. Cathepsin K inhibitors for osteoporosis and potential off-target effects. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110777/
  5. ClinicalTrials.gov. (2006). GlaxoSmithKline. Study To Determine The Effects Of Doses Of Relacatib On The Metabolism Of Acetaminophen, Ibuprofen And Atorvastatin. Available at: https://clinicaltrials.gov/ct2/show/NCT00411190?term=Relacatib&rank=1
  6. ClinicalTrials.gov. (2013). Merck Sharp & Dohme Corp. Efficacy and Safety of Odanacatib in Postmenopausal Women Previously Treated With Oral Bisphosphonate (MK-0822-076). Available at: https://clinicaltrials.gov/ct2/show/NCT01803607?term=Odanacatib&rank=1

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References (cont.)

7) Drake et al. (2017) Cathepsin K Inhibitors for Osteoporosis: Biology, Potential

clinical Utilities and lessons learned. Endocrine Reviews Vol. 38(4) 325-350.

8) What is Osteoporosis and What Causes It? from:

https://www.nof.org/patients/what-is-osteoporosis/

9) Andrés Felipe Posadaa,,Hernán Darío Aguirre, Julio Cesar García Casallasc,Jhon

Darío Lodono ,Patino , Rafael Valle Onate New therapies in osteoporosis.

10) Diseases and Technologies Retreived from

http://thecureisnow.org/our-strategy/diseases-and-technologies

11) NCBI. (2011) Leung P et. al. The effects of the cathepsin K inhibitor odanacatib on

osteoclastic bone resorption and vesicular trafficking. Available at https://www.ncbi.nlm.nih.gov/pubmed/21718816

12) NCBI. (2016) Duong le T et al. Cathepsin K inhibition: A New Mechanism for the

Treatment of Osteoporosis. Available at https://www.ncbi.nlm.nih.gov/pubmed/26335104

13) NCBI. (2009). Bromme, D et al. Cathepsin K inhibitors for osteoporosis and potential

off-target effects. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110777/

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References (cont.)

14) What makes a good drug target? Drug Discovery Today Volume 17S

February 2012. Retrieved from https://medschool.ucsd.edu/vchs/research-services/funding-opportunities/Documents/DrugDiscoveryToday.pdf

15) NCBI data bank: CTSK cathepsin K (homo sapience)

https://www.ncbi.nlm.nih.gov/gene/1513

16) International Osteoporosis Foundation: Facts and Statistics

https://www.iofbonehealth.org/facts-statistics#category-18

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