Post on 03-Jan-2016
description
1
vFLIP-IKK BlockerHelix Mimetic
Edith Chan
WIBR
2
Cleft1 Interactions• Residues involved in this region are
• F238 – all hydrophobic interaction, enclosed by F53, F79, L80, P54, and A57.
• D242 and K246 – enclosed by H83,T87,Y90,S89
• K246 has a H-bond with C=O of M88
• D242 has a H-bond to H83
• Mutation study showed that A57L has impaired the forming of the complex. P54G shows a reduction in affinity while Y90L retains affinity.
• D242R mutant has rendered IKK largely incapable of forming a complex.
Ala57L
Pro54G
Tyr90F
FQEYDNHIK
3
Aryl sulfonamides• Aryl sulfonamides have been used in both p53-HDM2 and Bcl-2 as inhibitors
• Cyclacel (Dundee) has developed good p53-HDM2 compounds that potently and selectively killed cancer cells through induction of apoptosis. There is no publication except a patent. The IC50 ranges from 20-100 M. How these compounds interact with the protein is not elucidated.
S
S
OO
N
R
R
R
SOO
NS
N+
O
O
Cl
F
FF
SOO
NS
F
FF
F
FF
Cl
N+
O
O
SOO
NS
H
N+
O
O
Cl
S
S
OO
N
R
R
R
4
First series - Conformations
SOO
NS
H
N+
O
O
Cl
• This compound has mainly two rotatable bonds.
• Conformational analysis showed that there are mainly 2 classes of conformations.
• The lower energy ones – 2 rings come closer together – a bent conformation
• The higher energy ones adapt more linear geometry
S
S
OO
N
R
R
R
5
2nd series - Conformations• This compound has a couple of
rotatable bonds, however, it is more rigid than one thought.
• After performing conformation analysis, there are mainly two classes of conformations – in either cases, two of the aromatics rings will face each other as hydrophobic collapse.
• The lowest energy one has phenyl and thiopene rings facing each other.
• The higher energy one is two phenyl rings facing each other. The two CF3 groups repel each other.
• Again, both are bent comformation.
SOO
NS
F
FF
F
FF
Cl
N+
O
O
S
S
OO
N
R
R
R
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X-ray confirmation
• There are quite a nuber of structures that have sulfonamides in the X ray database.
• Shown here are two different structures – similar to series 1 and 2 mentioned above.
• Both X-ray show a bent conformation.
SO O
N
S
N+
O
O
O
O
S
O O
N
O
N
ON
O
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Overlays with helix peptide
• The bent conformation of the sulfonamides is a good mimic for 2 of the residues on the IKK- helix -FxxxDxxxK
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Compound Acquisition
• Limited selection with thiopene substitution – search with phenyl.
• R1 and R2 – a combintion of – acidic
– polar
S
N+
N
O
O
O
O
S
S
OO
N
R
R
R
S
OO
N
R2
R3R1
S
N
O O
NH O
SN+
N
O
OO
O
S
N
O O
O
OH
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Search strategy
• Search with substructure (- all those not wanted
• - MW <550 and rb < 6
S N
O
O
NS
O
O
NN
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• p53-HDM2 inhibitor
• IC50 = 100-300 nM• Best compound – 4-(S),5-(R)-
imidazoline• Racemic mixture will also work• Oral administration of 200 mg/kg
twice daily for 3 weeks on mice was well-tolerated
• This treatment of mice established with tumours resulted in 80% inhibition of tumour growth.
N
N
R
R
NO N R2
O
R3
Nutlins
• Nutlins are named geographically after Hoffmann-La Roche’s research site in Nutley, N.J.
• This series of compounds are the only p53 mimetic that have in vivo activity
• Although these are custom synthesized compounds, a few of them can be obtained from the NCI for free.
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N
NBr
Br
N
O
N
O
O
O
1rv1
Nutlins – X-ray structure
Phe(Phe)(Asp)Trp
(Lys)Leu
Phe Trp
Leu
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NCI compounds
N
N
N
N
ON
N
NS
N N
N S
H
N
NS
N N
N S
H
9054 627018
650819 650820
N
NMeO
MeO
OMe
Aurora feinchemie 586999
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IC50 ~ 20uM (p53-HDM2)
Isoindolinones
N
O
O
Cl
O
O
N
O
NO
RN
O
O
R2
N
O
O Phe(Phe)
Trp(Asp)
Leu(Lys)
PhePheAsp
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Some examples
N
NH
O
O
N
CH3
N
NH
O
O
O
O
CH3
N
NH
O
OO
O
OCH3
CH3
N
O
OHO
O
O
CH3
CH3