Bexarotene Targretin

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Bexarotene Targretin

• Drug acts at nuclear receptor

Laksirin Sirisatean 4550076
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FDA approved

• Primary cutaneous T-cell lymphoma
• (CTCL)

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What is CTCL ?

• non-Hodgkins lymphoma composed of malignant T
  lymphocytes of the CD4 phenotype
• serious but uncommon skin condition

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Pathogenesis
epidermal growth factor
endogeneous INF-?
cell proliferation and differentiation
block T cell
cell cycle and apoptosis
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Pathogenesis
genetic alteration
CTCL develop
INF-? resistance
epidermal growth factor
defect
cell cycle regulation and apoptosis
T-lymphocyte proliferate
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Pharmacological effect of retinoid
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Physiological of RAR-RXR

• control abnormal cellular process by
• Modulating cell differentiation
• Inhibiting cell proliferation
• Regulating apoptosis

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CTCL includes

• Mycosis fungoides
• Sézary syndrome
• Follicular cell lymphoma
• T-cell leukaemia

DermNet Editorial Board Department of Dermatology,
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Clinical Manifestations
patches
infiltrated plaques
tumors
Journal of the Moffitt Cancer Center
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Treatment

• Topical steroids
• UVB phototherapy
• PUVA photochemotherapy
• Topical nitrogen mustard
• Chemotherapy
• Localised radiotherapy
• Electron beam radiotherapy
• Interferons
• Oral retinoids
• Bone marrow / Stem cell transplantation
• Photopheresis.

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Bexarotene (Targretin?)

• First synthetic highly selective RXR retinoid

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Synthesis
4-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-nap
hthalenyl)-1-propenylbenzoic acid
TTNPB
R
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Synthesis

AlCl3
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Synthesis

AlCl3
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Synthesis

NaNH2 THF
Ph3PCH3Br
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Synthesis

HCl
KOH, MeOH
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R

etinoid

RXR Agonist
eceptors
TARGRETIN
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R
etinoid

Type
eceptors
2 Type
The Retinoic Acid Receptors

The Retinoid X Receptors

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R
etinoid
eceptors
RXR Receptor Structure
Ligand-Binding Domains

DNA-Binding Domains

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R
etinoid X

Structure
eceptors
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R
etinoid X
eceptors
Ligand-Binding Domains
Ligand- Binding Pockets
L-Shaped Form
H3 H5 H7 H11
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R
etinoid X
eceptors
CH2
R
Drug
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R
etinoid X
eceptors
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R
etinoid X

eceptors
DNA-Binding Domains
2-Zinc finger motifs
P box
D box
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R
etinoid X
eceptors
DNA-Binding Domains
Direct Repeat
5 base-pairs
5
3
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R
etinoid X
eceptors
DBD Structure
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R
etinoid X
eceptors
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R
etinoid X

eceptors
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Mechanism Of Action
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R
AR-RXR
HDAC
CoR
RXR
RAR
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R
AR-RXR
HAT
CoA
Drug
RAR
RXR
Transcription
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Conclusions