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Proteasome pharmacology
- 1. Proteasome pharmacology Dr Manish Mohan
- 2. Contents • Introduction • Proteasome structure • Drugs • Antimalarial drugs
- 3. Introduction • Homeostasis between protein synthesis and degradation is a pivotal cellular process involving a multitude of precise and highly complex regulatory processes • Ubiquitin proteasome system (ups) ∼80% • Proteasome, a large, tightly regulated protein complex • 2.5 MDa
- 4. Cont…… • Proteins are targeted for proteasomal degradation • Covalent attachment of the 8.5 kDa protein ubiquitin • ubiquitin-activating enzyme(E1) • Ubiquitination ubiquitin-conjugating enzyme (E2) ubiquitin-protein ligase(E3)
- 5. Cont….. • Proteasome • Cytoplasm + Nucleus -----Eukaryotic Cells • 20S core particle (CP) • 700 kDa and comprises 28 protein subunits
- 7. constitutive proteasome immunoproteasome ThymoproteasomeAll tissues monocytes and lymphocytes cortical thymic epithelial cells
- 8. To prevent uncontrolled degradation of cellular proteins, access to the 20S CP is tightly regulated. 19 S Regulatory Particle
- 10. • The proteasome is pivotal for intracellular protein homeostasis as it eliminates misfolded proteins • Endoplasmic reticulum (ER) stress • Unfolded protein response • NFκB inhibition • Cell cycle arrest • Increase in proapoptotic factors and tumor suppressors
- 13. First Generation • Bortezomib • Proteasome-mediated protein degradation • Treatment of MM (FDA in 2003)
- 14. Mechanism of Action Binds to the β5 subunit of the 20S core of the 26S Reversibly inhibits its chymotrypsin-like activity Multiple intracellular signaling cascades(-) Apoptosis
- 15. Cont…… • Consequence --------- Effect On NF-κB, Cell Damage Response And Cell Survival • NF-κB is cytosolic and bound to IκB • Bortezomib blocks proteasomal degradation of IκB • Accumulation of BAX (apoptosis promoter)
- 16. ADME • Dose -1.3 mg/m2 • Intravenous bolus on days 1, 4, 8, and 11 of every 21-day cycle • The drug exhibits a terminal t1/2 in plasma of 5.5 h • Peak proteasome inhibition reaches 60%----1 hr
- 17. Cont…. • Bortezomib clearance ------deboronation of the parent compound (90%) hydroxylation CYPs 3A4 and 2D6
- 18. Therapeutic Uses • MM (over expression of NF-kB) • MM after relapse from other drugs • Relapsed or refractory MCL
- 19. Adverse Effects • Thrombocytopenia (28%), fatigue (12%), peripheral neuropathy (12%), • Neutropenia, anemia, vomiting, diarrhea, limb pain, dehydration, nausea • Peripheral neuropathy • Injection ----- precipitates hypotension • Congestive heart failure and prolonged QT interval ---reported.
- 20. carfilzomib • irreversible proteasome inhibitor • second-generation selective proteasome inhibitor • Mechanism : • It targets the β5c and β5i subunits of the 20S CP
- 21. Cont….. • Route ---IV • T1/2-30 min • Orally Available Carfilzomib Analogue- Oprozomib
- 22. Adverse effects • Thrombocytopenia • Diarrhea • Dyspnea • Anemia • Peripheral edema
- 23. Ixazomib • Orally bioavailable • Second-generation peptide analogue proteasome inhibitor • MOA - interacts with subunit beta type 5 (PSMB5) of the 20S proteasome complex • Elimination half-life : 9.5 days
- 24. ADVERSE EFFECTS • Diarrhea • Peripheral neuropathy • Hepatotoxicity.
- 25. Salinosporamide • The only nonpeptidic proteasome inhibitor in advanced clinical trials for MM • Also known as marizomib • Orally available • Very short half-life---- < 15 min • Penetrate BBB MOA -irreversibly via an ester and tetrahydrofuran formation
- 27. IPSI-001 • β1i selective • Accumulation of ubiquitin–protein conjugates and proapoptotic proteins • Caspase-mediated apoptosis in in vitro models of hematological malignancies
- 28. ONX0914 • 100-fold increased selectivity beta1i >>>beta1c
- 29. Others….
- 30. Omacetaxine • Inhibition of protein translation • By preventing the initial elongation step of protein synthesis • Thereby depleting the cell of short-lived proteins • Use ------- Chronic or Accelerated -phase CML
- 31. Capzimin • Deubiquitinase activity of rpn11 • Rpn11 is the only deubiquitylating enzyme present in the 26s proteasome • Capzimin proved active against several cancer cell lines, including bortezomib-resistant cell lines
- 33. MALARIA • Malaria parasite Plasmodium falciparum • PR3----carfilzomib analogue • Effective in killing parasites while having only minor effects on host cells • β5 inhibition as effective during the replication stage • simultaneous β2 and β5 inhibition resulted in enhanced parasite killing at all stages
- 34. Summary • Proteasome • Structure • Drugs • Antimalarial drug
- 35. THANK YOU
Notas del editor
- The catalytically active subunits are β1 (CL), β2 (TL), and β5 (ChTL) β1, β2, and β5 that exhibit caspase-like (CL), trypsin-like (TL), and chymotrypsin-like (ChTL) activities
- Open the proteasome for substrate degradation in an ATP- and ubiquitin-independent manner
- Bortezomib is a reversible dipeptide boronate inhibitor
- inhibitor of nuclear factor kappa B
- bor-tezomib in the dorsal root ganglia cells, mitochondrial-mediated disregulation of Ca++ homeostasis, and disregulation of neurotrophins
- first orally available proteasome inhibitor