Van der Wals

Ionic interaction

Hydrogen bonding
Effect
Various targets Drug-target complex

Effect
https://
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Hydrophobic
region
 Ser
Ser

O OH
H-bonding H HO OH
H-bonding
H
O O H

π-π interactions

Phe
HO

H O O
O H2N
Ionic interactions

O
H2N Asp
NH2
Asn

Hydrophobic
region
 O

N N

O
O
N HN N N

HN O
O
N HN

HN O

OH

H O O
N
O
N O

O N N
O

N O
N HN
N
N
HN O
O
O
HN
O
O
N HN O
O O
O N O
O
N N
HN
O
O
 O
O
O

N NH O O
O
OH N N O O
NH
O
N O
N NH O NH
O O O
N N
NH

N NH O
O
N N
NH
O

N O
N N
O HN
O N
O O
N N
N O
O HN

HN

O
 One Three Stage One Stage Two NH Stage Three NH

N
N
O
NH N NH N
O NH
N O N O O N
O O O
N NH O
O

O N O
O
Previously synthesised a NH
O O
N
N
N

HO O
NH
N O
N
O Attachment O
N NH point N
OH NH
O
O N O O
N O N
O H
Starting point for PRTOACs S

GSK warhead 1st generatino of PROTACs Potential target

 Identification of
O
attachment point
N N
Amide coupling
O O
N HN
N N Borylation, oxidation
HN O

GSK probe SNAr O

N HN

HN O
1st generation of
OH
O PROTACs
N N

O
O
N HN N N

O Alkylation
HN
O
O
N HN

N HN O
N
N
O

O O
O O
O
O N O
N
O O
N O
H O
HN

2nd generation O

Click reaction of PROTACs Alkylation

 O

N N Amide coupling

O
O
N HN N N Borolation, oxidation

HN O SNAr
O
N HN

HN O
Click reaction
OH

H O O
N
O
N O

O N N
O
Alkylation

N O
N HN
N
N
Amide coupling
HN O
O
O
HN
O
O
N HN O
O O
O N O
O
N N
HN
O
O
 Identification of attachment
O point

N N Amide coupling

O
O
N HN N N Borylation, oxidation

HN O SNAr
O
N HN

GSK probe HN O
Click reaction 1st generation of PROTACs
OH

H O O
N
O
N O

O N N
O
Alkylation

N O
N HN
N
N Amide coupling
HN O
O
O
HN
O
O
N HN O
O O
O N O
O
N N
HN
O
O
2nd generation of PROTACs
 NH
NH
Stage One Stage Two Stage Three N
Stage Four
O N
N NH
NH O
N
NH
O N O O N
N
O NH
O O
O
N NH O
N
O N O
a NH
O Attachment
point O O
O
N N N
Previously synthesised OH N
O N O HO NH O
N O O
Starting point for PRTOACs O HN N
NH
O O
O
N
S

GSK6853 GSK warhead 1st generatino of PROTACs Potential target

 NH
NH
Stage One Stage Two Stage Three Stage Four
N
O N

N NH
N
NH O NH
NH O N O O N
N O O
N O
O
O Attachment O
N NH
N NH point
N OH O
O O
O N O N
O O N
42 43 N
HO NH O
O O
Originally synthesised N
Starting point for PRTOACs
by GSK O HN N
NH
O O
O
N

44 S

GSK6853 BRPF1 warhead 1st generation of PROTACs 2nd generation of PROTACs