Transcription Factors and Neoplasia: Vistas in Novel Drug Design
Novel Drug Design
description
Transcript of Novel Drug Design
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Novel Drug Design
Modified Megestrol
by
Group II
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Introduction
Hepatocellular carcinoma
Occur almost in patients witn - Chronic hapatitis virus C and/or B infection - CirrhosisRepresent the final step of the natural course for virus induced liver disease
500000More than , people are diagnosed each year tttttttttt ttt t tttt and over a million death per yearMore common in developing country in Africa and East asia
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More frequent in men than in womenNo specific drug for the treatmentRisk factors: - HVB - HVC - aflatoxin - alcohol - sex hormones
Geographic distribution of hepatocellular carcinoma.Incidence rates (%) in total population A, female; B, male.
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Estrogen Receptor (ER)
Receptor for estrogen located intracellular in many
organs
Contain a specific site to which only estrogens
(or closely related molecules) can bind
Act as a transcription factor, regulate the reading
of DNA and production of protein
Two different ER are usually call and receptor
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Estrogen function assignaling molecule
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Estrogen Receptor in Liver
ER has been well characterized in human liver
Normal Liver wild-type ERs
Hepatocellular carcinoma
wild-type ERsVariant form of ER (vER) exon 5 deletion (ER5)
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Variant from of Estrogen Receptor and Hepatocellular carcinoma
vER largely predominates in HCC vER appears most frequent in patients infected with Hepatitis B virus Growth rate of HCC in patient with vER higher than patient with wtER vER elevate proliferation rate tumor aggressiveness lack of hormonal control on tumor growth (ER5) ---- > lack the hormone binding domain but being intact in the DNA-binding domain
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Chemotherapy
“The use of chemical substances to treat the disease”
Types
Alkylating agentsPlant Alkaloids Antitumor AntibioticsAntimetabolitesTopoisomerase inhibitorsMiscellaneous Antineoplastics Hormonal therapy
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Alkylating agents Add alkyl groups to many electronegative groups e.g Nitrogen mustard (cytotoxic chemotherapy)
Hormonal therapy
e.g. Tamoxifen Megestrol acetate
Competitive binding to the receptor and block the action of hormone and thereby interfere with, or even prevent, the proliferation of cancer cell
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Megestrol acetate
A synthetic female hormone belonging to the progesterone group
Survival of HCC patients therapy with megestrol acetate is increase
Slowdown tumor growth
Drug able to block both wtER and vER
Anti estrogen action
Usually for women whose cancers do not respond to the other hormone treatments
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Bifunctional molecule
Produce DNA adducts Specific bind the estrogen receptor
- Inhibit DNA repair - Induction of growth inhibition, apoptosis and antitumor activity - Consist of => War head => Linker => ligand binding domain
Modified Megestrol
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Presentation Outline
- Production Ms. Jittima Khorungkul
- Mechanism Testing of the Drug Mr. Pasavi Ratchapongsirikul
- Preclinical Study Ms. Sirikan Nawapan
- Clinical TrialMs . Carolina Rusdy Akib - Marketing
Mr. Mahinda Chandrasiri Edirisooriya
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Production
of
Modified Megestrol
by
Jittima Khorungkul
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Modified MegestrolProduction
Goal: Synthesis bifunctional molecule that can use in Liver cancer treatment
Bifucntional molecule: Produce DNA adduct Specific binding the estrogen receptor with high affinity
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Megestrol Estrog
en rec
eptor
DNA adduct
Binding to vER
Bifunctional molecule structure
Ligand Domain
Linker
War Head
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Expression of essential
gene
Undamaged cellUndamaged cell
Nuclear protein (e.g.ER)
promoter
How modified megestrol work…..
Estrogen and ER complex
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Adduct shielded from Adduct shielded from RepairRepair
DNA repair enzyme
Adduct persists
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Adduct shielded from RepairAdduct shielded from Repair
In non-cancer cell
(less express of vER)
DNA repair enzyme
adduct
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Adduct shielded from Adduct shielded from RepairRepair
Cancer cell(over express of vER)
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Adduct “Hijacks”Adduct “Hijacks”Transcription FactorTranscription Factor
X
Cancer cell(over express of vER)
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Modified megestrol
N,N -bis-chloroethylaniline (War Head)
Alkyl-amino-carbamate (Linker)
Megestrol acetate (Ligand Domain)
Consisted of :
(CH2)6-N-(CH2)2-0 N-(CH2)3- -N
H O H (CH2)2
Cl
(CH2)2
ClLigand Domain Linker
War Head
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Modified megestrol
Megestrol acetate (Ligand Domain)
-Binding to the linker at 7 alpha position Large alkyl groups can be attached with retention of high affinity for ER
Megestrol acetate
7 alpha position
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Modified megestrol
N,N -bis-chloroethylaniline (War Head)
- Ability to alkylate DNA- From covalent DNA adduct at the N7 position of guanines
N
Cl
Cl
N,N -bis-chloroethylaniline
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Modified megestrol
Alkyl-amino-carbamate (Linker)
Consist of - amino - carbarmate group provide a relatively rigid connection resistant to hydrolytic enzyme
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Synthesis Procedure
(1) (2) (3)
(4) (5)
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Synthesis Procedure
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Synthesis Procedure
Final Product: Modified megestrol
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Properties of Modified Megestrol
Chemical Formula: C42H65Cl2N3O4
Exact Mass: 745.44Molecular weight: 746.89Element Analysis: C, 67.54; H, 8.77; Cl, 9.49; N, 5.63; O, 8.57
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Summary
H
CH3
H3C
H
H
H3C OH
(CH2)6NH(CH2)2O
O
NH
NCl
Cl
O
Modified Megestrol
-Modified Megestrol is the bifunctional molecule thatconsist of ‘Warhead’, ‘Linker’ and ‘Ligand binding domain’ -It has the abilities to produce DNA adduct and capable ofbinding the vER - vER-DNA adduct complexes will shielded from DNA repair enzyme
War head
LinkerMegestrolacetate