1. Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors
School of Pharmacy, Sungkyunkwan University
Fri. seminar.
Park Sook Jin

2. INDEX 01 About BET inhibitor 02 Paper work - Abstract
03 Paper work – Introduction & Discussion
04 Paper work - Conclusion

3. Part 1
About BET inhibitor

4. PART1. About BET inhibitor
Write emzymes : HATs, HMTs and Kinases
Eraser enzymes : HDACs, DMTs, phosphatases
Reader proteins : bromodomains, chromodomains, PHDs, etc.
For instance, HATs deposit acetylation marks on lysine residues, which are ‘read’ by bromodomain modules and removed by HDACs.

5. PART1. About BET inhibitor
“Bromodomains”
: readers of acetyl lysine residues
→ The recognition of N-acetylation of lysine residues is primarily initiated by bromodomains.
“Functions of bromodomains”
► Proteins that contain bromodomains are involved in the regulation of transcription - A key role in the development of cancer.
► Bromodomain-containing proteins regulate NF‑κB, which is a key transcription factor that mediates inflammatory responses.
This suggests that targeting these proteins could be development of new treatment strategies for cancer, inflammation and viral infections.

6. PART1. About BET inhibitor
► Domain organization of BET proteins. The name and length of the proteins are shown together with the position of their first and second bromodomains.
BET FAMILY (Bromodomain and Extra-Terminal)
► BRD2, BRD3, BRD4 and BRDT
Each of which contains tandem bromodomains (BD1 and BD2) that recognize specific acetylated lysine residues in the N-terminal tails of histones.
★ Control expression of genes critical for proper cell growth
★ Reduction of their levels or inhibition of their activity has profound effects on cell proliferation and viability.

7. PART1. About BET inhibitor
Structure of bromodomains
► four α-helices
αZ, αA, αB and αC
► linked by diverse loop
ZA loop and BC loop
★ participate in acetyllysine reader
pocket formation
★ recognition elements for the modified
peptide sequence
★ green triangle : approximate location of acetyllysine binding pocket.

8. PART1. About BET inhibitor
Model of BET mechanism of action.
BRD4 protein recruits positive transcription elongation factor b (P-TEFb), an essential step in RNA Pol II–mediated transcriptional elongation.
A BET inhibitor blocks the binding of BRD4 to acetylated lysines on nucleosome histones, inhibiting RNA Pol II–mediated transcription.

9. PART1. About BET inhibitor

10. PART1. About BET inhibitor

11. PART1. About BET inhibitor
BRD4 inhibition modulates MYC transcription in Acute Myeloid Leukemia.
BRD4 mediates bromodomain-dependent MYC transcription, and BRD4 inhibition with JQ1 results in decreased MYC transcription in Acute Myeloid Leukemia cells.

12. Part 2
Paper work - Abstract

13. Paper Work - Abstract

14. Paper Work - Introduction
In 2009, the Mitsubishi Tanabe Pharma
Corporation reported the first small molecule inhibitors of this family of chromatin adaptors, and publications followed on the use of BET inhibitors to demonstrate antitumor activity and
modulate inflammation.
(+)-JQ1

15. Paper Work - Introduction

16. Paper Work - Introduction
Key interactions for
(A) triazole 2 (PDB: 3P5O)
(B) dimethylisoxazole 39 (PDB: 3ZYU)
(C) pyridone-like 40 (PDB: 4E96).

17. Part 3
Paper work - Introduction

18. Paper Work - Introduction
★ Similar hydrogen bonding contacts with the asparagine(N) residue.
★ Isoxazole could serve as a replacement for the triazole.
★ 3,5-dimethyl isoxazole motif was preferred binding for bromodomains.

19. Paper Work - Introduction

20. Paper Work - Discussion

21. Paper Work - Introduction
3.2 Å
Van der Waal distance

22. Paper Work - Introduction
tyrosine
asparagine

23. PART1. About BET inhibitor

24. Paper Work - Discussion

25. Paper Work - Discussion

26. Paper Work - Discussion

27. Part 4
Paper work - Conclusion

28. Paper Work - Conclusion
★ Compound 3 is a potent and selective BET inhibitor in biochemical and cellular assays, has a rat and dog pharmacokinetic profile suitable for in vivo experiments.
★ inhibits MYC mRNA expression in vivo after PO dosing in a dose-dependent manner.
★ Further studies detailing the optimization and development of 3 and related compounds will be reported in due course.

29. Paper Work - Conclusion

30. Paper Work - Conclusion
Optimization of metabolic stability
Pharmacodynamic effect in a mouse model of IL-6 suppression

31. Paper Work - Conclusion

32. Paper Work - Conclusion
molecule
structure
OTX-015
GSK
CPI-0610

33. Thank you