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vFLIP-IKK g Blocker Helix Mimetic

vFLIP-IKK g Blocker Helix Mimetic. Edith Chan WIBR. Cleft1 Interactions. F QEY D NHI K. 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

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vFLIP-IKK g Blocker Helix Mimetic

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  1. vFLIP-IKKg BlockerHelix Mimetic Edith Chan WIBR

  2. Cleft1 Interactions FQEYDNHIK • 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 IKKg largely incapable of forming a complex. Pro54G Tyr90F Ala57L

  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 mM. How these compounds interact with the protein is not elucidated.

  4. First series - Conformations • 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

  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.

  6. 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.

  7. Overlays with helix peptide • The bent conformation of the sulfonamides is a good mimic for 2 of the residues on the IKK-g helix -FxxxDxxxK

  8. Compound Acquisition • Limited selection with thiopene substitution – search with phenyl. • R1 and R2 – a combintion of • acidic • polar

  9. Search strategy • Search with substructure (- all those not wanted • - MW <550 and rb < 6

  10. 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. 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.

  11. Nutlins – X-ray structure 1rv1 Phe Trp Leu (Lys)Leu (Asp)Trp Phe(Phe)

  12. NCI compounds 9054 627018 650819 650820 Aurora feinchemie 586999

  13. Isoindolinones IC50 ~ 20uM (p53-HDM2) Trp(Asp) Leu(Lys) Phe(Phe) Asp Phe Phe

  14. Some examples

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