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353 Exam 2
| Question | Answer |
|---|---|
| What is a therapeutic window? | Difference between minimum effective dose and maximum tolerated dose |
| Why does targeted chemotherapy have a larger therapeutic index compared to cytotoxic therapy? | Targeted therapy exploits the molecular differences between WT and cancer cells as opposed to targeting/killing all cancer cells. |
| Telomeres and telomerase are a solution to _______ problem. | End replication |
| What are the two components of telomerase? | Catalytic protein Integral bound RNA |
| What is the mechanism of function for telomerase? | 3' end of DNA base pairs with telomerase RNA Uses RNA as template to synthesize telomeric sequence. Telomerase realigns with newly synthesized sequence to continue elongation. |
| What does TERT stand for? | Telomerase reverse transcriptase |
| What are some considerations to keep in mind when targeting telomeres? | Efficacy may depend on initial telomere legnth. Cells will need to be exposed to the inhibitor for a long time before the telomeres critically shortened. |
| How can you predict how sensitive a cell will be to telomerase inhibition? | Southern blot or biopsy to determine telomere legnth. |
| How does telomerase inhibition work? | Degrade telomerase mRNA Telo rz Ribozyme specific to this mRNA, cuts it. mRNA no longer protected by cap or tail and therefore degarded. |
| Why might teloRZ work better at 37C? | Kinetics, Correct structure may form better at this temp. |
| How does BIBR1532 work? | Binds RNA binding surface of hTERT |
| What is the limitation of telomerase inhibiting drugs? | Not very potent as of yet |
| How does imetelstat? | 13mer that mimics telomeres |
| Why does imetelstat have a fatty acid side chain? | Help it get through phospholipid bilayer |
| What are NRTIs? | Nucleotide reverse transcriptase inhibitors Nucleotide analogs to reduce enzyme function. |
| What are G quadruplexes? | In G rich regions for G's stack on top of each other their hoogsteen and watson crick faces interact with one another. |
| How are G quadruplexes stabilized? | By telomestatin, pi stacks with them. |
| What is BCR? | Breakpoint cluster region Activity unclear |
| What is ABL? | Abelson murine leukemia virus Tyrosine kinase drives cell proliferation |
| How is ABL kinase activity increased? | by deleting N terminus during BCR ABL fusion |
| How does the N terminal domain autoinhibit ABL | N terminal domain modified with fatty acid myristoyl tag Tag binds pocket of kinase domain |
| How does imatinib resistance develop? | Point mutations in an near ATP binding site where the drug binds Gene amplification. |
| How does asciminib work? | Binds myristoyl binding pocket Not affected by mutations. |
| How does imatinib/gleevec work? | It binds the ATP binding pocket of ABL kinase. It does so in its inactive conformation preventing it from being activated. BCR/ABL is anti apoptotic removing it induces apoptosis. |
| Nilotinib | Imatinib redesigned for higher potency. |
| Dasatinib | Binds both active and inactive forms of ABL kinase. |
| Is Asciminib affected by ATP conc? | No it binds the myristoyl binding site not the ATP binding site. |
| What is another advantage of asciminib? | Higher specificty, myristoyl actvities much more specific to BCR ABL then ATP activity. |
| What kind of kinases are EGFR? | Receptor tyrosine kinases |
| What binds EGFR? | GRB2 then SOS which actiavtes Ras |
| What is Ras bound to when active? | GTP |
| What does active MAPK do? | Localizes to nucleus, activates TF Fos/Jun. |
| What does Ras activate? | Raf, PI3K |
| What is the relationship between Her2 and EGFR? | Very similar structurally and biologically Can dimerize with one another Both RTKs Different proteins on different cell types |
| What is Herceptin? | Trastuzumap Monoclonal antibody that binds Her 2 |
| What kind cancers is Herceptin used for? | Breast and stomach |
| How does Trastuzumab inhibit release of CDK2? | Prevents activation of AKT. AKT no longer inhibits p27 p27 inhibits Cylcin E leading to inhibition of CDK2 |
| How may Trastuzumab lead to some cell killing? | Binding attracts immune cells to the antibody leading to apoptosis |
| How does Herceptin resistance develop? | p27 stops localizing to the nucleus |
| How does Trastuzumab emtansine / deruxtecan work? | Trastuzumab is the ab that delivers the payload of maytansine cytoxic therapy. Linked to T with linker. Binds to receptor, receptor endocytosed, degraded by lysosome leaving peptide fragments, considered release of the drug. |
| Where to Gefitinib and Erlotinib bind? | Intracellular ATP pocket of EGFR competitively |
| How do Gefitinib and Erlotinib work? | Inhibits autophosphorylation Mimic ATP |
| Why do cancers with mutations in EGFR kinase domain respond better to Gefitinib and Erlotinib ? | Tumor cells more sensitive to lack of ATP binding Structural changes improve affinity to Gefitinib and Erlotinib |
| What mutation causes resistance to Gefitinib and Erlotinib ? How? | T790M, Methionine obstructs binding site + Mutation makes ATP bind better |
| How are Gefitinib and Erlotinib improved? | Allow them to bind EGFR covalently as opposed to reversibly Then Optimised to bind T790M |
| Why might kinases still be good targets despite kinome? | Generally okay if within toxicity window May help with resistance, drug may alr bind to the new thing Can help treat multiple cancers |
| Most common mutation in BRAF | V600E |
| How does Ras activate BRAF? | Recruits a lot of it Dimerises Activation segment helix stops blocking active site due to conformational change |
| Why does V600E mutation affect BRAF? | Inactive state stabilised by hydrophobic interactions Glutamate stabilizes active state regardless of Ras |
| Sorafenib | Binds ATP binding pocket of BRAF Stabilises inactive form |
| Vemurafenib | Binds ATP binding pocket of BRAF better Affinity to V600E |
| What is alarming about vemurafenib? | Increases egfr pathway actvity in WT cells that dont have V600E mutation. It causes more BRAF to localise to PM dimerise with CRAF and activate pathway. |
| Why are Ras mutations oncogenic? | Affect its ability to hydrolyze GTP GDP state inactive |
| What is the opportunity with a Ras G12C mutation? | Things can covalently bind to cysteine WT Ras not bound by these, wide therapeutic window |
| How might drugs that stabilize the Ras ON state work? | They block Raf binding |
| What is TANGO | algo to predict aggregation-binding to itself |
| How do KRAS Pept ins work? | Mimic aggregation prone regions to induce aggregation |
| How does RNAi work? | It is mechanism to degrade foreign nucleic acids They get processed-chopped up loaded onto argonaute which has endonuclease domains RNA fragment guides it to foreign RNA to degrade |
| BCL2 is ___________ apoptotic | Anti |
| How is BCL2 targeted | siRNA |
| Challenges with RNAi? | RNA molecules not stable in cell susceptible to degradation Cannot always get into cells easily |
| What are some delivery methods for RNA? | LNPs |
| Active VS Passive Targeting of RNA delivery? | Active- has a molecule that binds something in the tumor cells Passive-get into tumor cells due to leaky vasculature |
| GalNAC | Binds receptor on cancer cell Endocytosed RNAi in the cell |
| How is siRNA prevented from degradation? | 5' cap, but not m7g so doesn't get translated 3' backbone linkages changed Methyl and phosphothioate to prevent hyrolysis |
| Patisiran | Methylated siRNA + lipids |
| Why does GalNAC work but other si RNA drugs have slow release? | The liver cell receptor it binds to is very abundant |
| What are two ways to improve endosomal escaape? Why don't they work? | Endolytic peptides, Enveloped viruses Can be cytotoxic and trigger antigenic response |
| CRISPR Cas 9 | Guide RNA loaded onto Cas 9 endonuclease to target whatever we want Breaks target DNA fixing by NHEJ leads to indels Lead to inactive protein |
| dCAS9 | Deactivated Cas 9 fuses to target DNA TF, histone modifier, deaminase |
Created by:
kashix