Kinase Inhibitors [NEED TO FINISH] Flashcards
What is one key structure that all the kinase inhibitors have in common?
- Have away to mimic ATP binding
In what way is cell singaling largely driven by?
- The ransfer of phosphates via ATP
What is the most common target of Kinase activity?
- Tyrosine
- Also Serine and Threonine
What way is there balancing of kinase activity?
- Phosphatases remove phosphates = oppse the action of the kinases
What are the types of Kinase Inhibitors?
- Type I: Bind to the active kinase
- Type II: Bind & stabilize the inactive kinase
- Type III: allosteric binding
What amino acids is not a target of phosphorylation?
- Alanine
What is the source of the phosphate that gets transferred onto a substrate by a kinase?
- ATP
What are the EGFR kinase inhibitors?
- Gefitinib, Afatinib, Osimertinib
What is Gefitinib?
- Type I TKI
- Re approved for NSCLC in 2015
What is Gefitinb used for?
- Treatment of EGFR mutant metastatic NSCLC
What is the mechanism of action for Afatinib?
- Covalent inhibitor for ALL EGF receptors
What is Afatinib used for?
- Treatment of EGFR mutant metastatic NSCLC
What are some tests that you should take to see if Afatinib could be useful?
- Exon 19 deletion
- Exon 21 substitution
For the EGFR kinase inhibitors, is a rash a good thing to have?
- YES; it should that the drugs is actually working within the body
In what way is there resistance toward Gefitinib and Afatinib?
- T790M
- Exon 19 deletion & Exon 20 substitution GOOD
What EGFR kinase inhibitor could you use to get around the T790M resistance?
- Osimertinib - comformation is different
What is Osimertinib?
- 3rd Gen EGFR inhibitor
- Covalent inhibitor
What is Osimertinib used for?
- Treatment of EGFR mutant metastatic NSCLC that HAS the T790M resistance mutation [1st line]
What is HER2 mostly found in?>
- Breast Cancer
What are the drugs that affect HER2?
- Lapatinib & Tucatinib
What is the mechanism of action for Lapainib?
- Binds to BOTH HER2 and EGFR inhibiting them but is selective for HER2
What is Lapatinib used for?
- HER2 Selective breast cancer
- Treatment of metastatic breast cancer with Capecitabine
What are some of the side effects for Lapatinib?
- Diarrhea, Nausea, Vomiting [blocking BOTH]
- Decreased Cardiac function [HER2}
What are Dacomitinb, Neratinib & Afatinib approved for?
- Dacomitinib & Neratinib = Breast and Lung
- Afatinib = NSCLC
What is the mechanism of action for Tucatinib?
- Binds ONLY to HER2 and blocks it - HER2 selective
What is the way that Tucatinib is used?
- 2nd line treatment for metastatic breast cancer with Trastuzumab & Capecitabine
What are some of the side effcets for Tucatinib?
- Less the Lapatinib BUT still cardio issues
What is FMS-like Tyrosine Kinase 3?
- Ligand that helps with Hematopoietic Cell Growth
- Mutation cause growth but NO death
What is the way that FLT3 gets mutated
- Internal Duplication [ITD] of the kinase receptor in juxtamembrane domain
What disease does FLT3 affect?
- AML: Acute Myeloid Leukemia
What are the FLT3 Inhibitors?
- Midostaurin [1st gen = TOO broad]
- Crenolanib [2nd gen = more specific]
- Quizartinib [3rd gen = FOR ITD mutation]
What is an example of Transolation of genes?
- Bcr-Abl
What is the special Chromosomal Translocation called?
- Philadelphia Chromosome [Ph1]: when 5’ Bcr is joined to 3’ Abl
- Found in 95% of chronic myeloid leukemia
What is the mechanism of action for Imatinib?
- [Type II]Inhibition of Abl that results in a decrease of proliferation and increase cell death in CML and GIST
What are some toxicities for Imatinib?
- Nausea & Vomiting
- Edema
- Neutropenia & Thrombocytopenia
What is important to know about Imatinib?
- LIFE LONG treatment
What is the mechanism of action for Ponatinib?
- The Bcr-Abl inhibitor
What is important to know about Ponatinib?
- Can inhibit the “gatekeeper” mutation T315I [which blocks Imatinib]
What is BRAF?
- Helps make RAF that increases cell growth
- BRAF v600 is the mutation
What is the mechanism of action for Dabrafenib?
- BRAF v600 inhibitor that blocks BRAF v600 but activates normal BRAF
What is the used of Dabrafenib?
- Treatment of Melanoma with BRAF v600
- Good for NSCLC with BRAF v600
- NOT for colorectal cancer with BRAF v600
What is the mechanism of Trametinib?
- Inhibits the kinase activity of MEK1 and MEK2
What is important to know about Trametinib?
- Used in combo with Dabrafenib?
- Type III inhibitor
What are the side effects for Trametinib?
- Rash
- Diarrhea
- Lymphedema
What is the importance of Bruton Tyrosine Kinase [BTK] in B cells?
- Helps with Normal B Cell activity and B Cell tumor growth
What are the BTK inhibitors?
- Ibrutinib & Acalabrutinib
What is important to know about Acalabrutinib?
- 2nd Gen Covalent BTK inhibitor
- Treatment for B cell lymphoma
- Stronger than Ibrutinib
What are the rapalogs?
- “limus”
- Inhibit the function of mTOR [Serine-Theronine Kinase]
- Can inhibit the immune response by blocking IL-2
What is unique feature of the rapalogs?
- Big ring structure
What is the major problem with Kinase inhibitors?
- Resistance: most of the time the dugs will work but can develop resistance causing symptoms to come back
