Assignment Group 2: Discovery and Development of Methotrexate on Psoriasis

1. Discovery and Development
of Methotrexate on Psoriasis
Azieyati Hani Binti Hussain (0326070)
Genevieve Tang Jia Yi (0325913)
Melissa Anne Bany (0325120)
Nurul Azzah Athirah Bt Mohd Nasir (0325888)
Teo Ting Ting (0326008)

2. Introduction
• Psoriasis: chronic inflammatory skin disease that causes red and crusty
patches of skin covered with silvery scales
• Methotrexate binds and inhibits the dihydrofolic acid reductase, able to slow
down the growth of skin cells in order to stop the skin from scaling
• Methotrexate usually taken orally, overdose result in dizziness, headache or
seizure

4. Disease Pathogenesis and Derivatives of
Methotrexate

5. Disease Pathogenesis
• Hyperplasia of T lymphocytes which leads to introduction of proliferation
of keratinocytes
• Chemokine called fractalkine, strong adherent force of leukocyte
• Bind to GPCR, triggering signalling pathway
• Trigger chemotaxis
• Large production of TNF-alpha
• Proinflammatory mediators such as IL-17/23

6. Derivatives of Methotrexate
• Autoimmune disease causes redness, scaly patches on skin
• Two types of therapy to treat psoriasis:
 Topical Therapy
 Systemic Therapy
• Belongs to a class of drug known as antimetabolites
• Works by inhibiting growth of cancer cells.
• Is a folic antagonist which is widely used to treat Psoriasis
• Rheumatrex analog of Methotrexate aid in Psoriasis

7. Discovery Pathway of Methoteaxate

8. Discovery Pathway
• In 1949, Sidney Farber, M.D. thought that by taking a folate inhibitor drug
like methotrexate would slow the cancer progress.
• Gubner reported that aminopterin utilized as a treatment as a part of
rheumatoid infection would likewise cleared psoriasis.
• In 1958, Edmundsun and Guy presented methotrexate which is a steadier
subordinate of aminopterin with lower lethality.
• In 1950s, this drugs were discovered to be effective in psoriasis patients and
in 1970s, it was eventually approved for psoriasis by the FDA.

9. Clinical Development of Methotrexate

10. Clinical Development
• Methotrexate that belongs to a class of drugs known as antimetabolites and works
by slowing or inhibiting the growth of cancer cells by suppressing the immune
system.
• Methotrexate is a folic acid antagonist which is widely being used to treat
autoimmune disorders like psoriasis.
• Psoriasis patients tend to have low level of folate that able to increase in
homocysteine.
• Analog of methotrexate such as rheumatrex which the generic name known as
methotrexate sodium able to aid in inflammation such as Psoriasis.

11. Protein Target and Mechanism of Action
of Methotrexate

12. Protein Target of Methotrexate
• Dihydrofolic acid reductase/ dihydrofolate reductase (DHFR)
• A protein/ enzyme
• Essential for:
 De novo mitochondrial thymidylate biosynthesis pathway
 Glycine synthesis
 Purine & pyrimidine nucleotide synthesis
• Plays an important role in DNA and RNA synthesis

13. Mechanism of Action of Methotrexate
• Has higher affinity for DHFR than dihydrofolic acid
• Binds to DHFR
• Inhibits DHFR enzymatic activity
• Dihydrofolic acids are not reduced to tetrahydrofolates
• Purine and pyrimidine synthesis will not happen
• One-carbon transfer reactions require specific coenzymes synthesized from
tetrahydrofolates
• Inhibit DNA and protein synthesis
• Cells are not dividing

14. • Methotrexate selectively affects the rapidly dividing cells such as
neoplastic and psoriatic cells
• Methotrexate:
 Slow down the proliferation of cells
 Stop the skin from scaling
 limit epithelial hyperplasia
 reinforce the apoptosis of activated T-cells
 inhibit the chemotaxis of neutrophils
• Decrease synthesis of tumor necrosis factor alpha (TNF- α) and
interleukin-1 (IL-1), which are involved in pathogenesis of psoriasis

15. Methotrexate
Related Drugs that are Under Development

16. Biologics
Tildrakizumab (MK-3222)
Phase II study
results were
satisfying, and is
now progressing
in Phase III.
Act as inhibitors
targeting the
unique IL-23
P19 subunit.
A monoclonal
immunoglobulin
G1 (IgG1) p19
antibody.

17. Biologics
Guselkumab (CNTO1959)
Reported to show
effectiveness in part one
of Phase III study, in
which a high proportion
of patients with
moderate-to-severe
psoriasis treated, had
clear or minimal disease
at week 16.
Lower percentage
of adverse effects
reported, compared
to Adalimumab at
Phase III study in
2015.
A human
monoclonal p19
antibody targeting
IL-23.

18. Biologics
Brodalumab
No major side effects
reported and has
been first launched
globally on
September 2016 in
Japan.
Published trials in
Phase II shows that
brodalumab seem to
have fast-acting
positive effects in
patients with
moderate to severe
psoriasis.
A monoclonal
antibody that binds to
IL-17 receptor and
inhibit inflammatory
signalling.

19. Small molecules
Tofacitinib
Act as inhibitor of
the JAK1 and
JAK3 signalling
pathway.
Obtained approval
for the treatment
of rheumatoid
arthritis in US.
Currently in Phase
III clinical trial for
plaque psoriasis
treatment.

20. Small molecules
KD025
A potent and highly
selective inhibitor of
ROCK2 (Rho-
associated coiled-coil
kinase 2)..
Now in Phase II clinical
trial, evaluating patients
with moderate-to-severe
psoriasis vulgaris.
Also evaluating
treatment for Idiophatic
Pulmonary Fibrosis and
Chronic Graft-versus-
Host disease.

21. Small molecules
CF101
A type of A3
adenosine
receptor
agonists.
Able to induce
apoptosis of
inflammatory
cells.
Has completed
its Phase II/III
clinical trial.

22. Conclusion
• Methotrexate is a folic acid antagonist that decrease in homocysteine and
allow the conversion of folic acid to tetrahydrofolate.
• Tofacitinib and tildrakizumab are potential drugs that able to cure psoriasis in
the future.
• Immunogenomics is another approach that identify autoantigens that trigger
psoriatic T-cell activation and expansion.