Kinase Inhibitors Flashcards

Question

How does Brc disrupt normal Abl function?

Answer 1

Bcl will be fused onto he N terminus which means N terminal doe snot act as a latch to prevent activation. This means that Abl will be active without the need for proline rich or phosphorylated tyrosine interaction and will be constitutively active

Answer 2

You get defective cell adhesion and growth factor independence as RTKs do not need to be activated for protein to function You get expansive growth and resistance of apoptosis

Answer 3

When tyrosine 412 is not phosphorylated

Answer 4

Allogenic stem cell transplant ion Interferon alpha Chemotherapy (<20% cured)

Answer 5

Imatinib (Gleevec) which inhibits Bcr-Abl

Answer 6

Chemo is no selective and targets all rapidly devising cells which included physiological haemopoetic stem cells. Thus normal stem cells not harbouring mutation will be destroyed. Imatinib only targets cells contains the bCr-Abl protein therefore benign cell survive and patient can have a fun ting immune system

Answer 7

Binds to the hydroxyl group on Threonine 315 via a hydrogen bind which blocks the ATP binding site T315 regulates ATP site access this binding to imatinib inhibits ATP binding and kinase activity

Answer 8

Complete cytogenetic response = 69% at 12 months 87% at 60 months Only 7% progress to accelerated phase or blast crisis over 5 years

Answer 9

``` Mainly mild to moderate ones Headache Dizziness Mouth ulcers Anaemia ```

Answer 10

Typically only Bcr-Able mutation in chronic phase As disease progresses more mutations occur which imatinib does not selectively target. These mutations are involve din other pathways which drive cancer

Answer 11

Does not eliminate Bcr-Abl cell so life long therapy needed (expensive) Less effective in blast crisis and Philadelphia + B cell acute lymphoblastic leukaemia Resistant CML does exist

Answer 12

Acute B cell lymphoblastic leukaemia

Answer 13

Additional mutations other than bcr-abl (>80% blast phase CML have mutations other than Philadelphia chromosome) Point mutation in Bcr-abl fusion protein T315I (gate keeper mutation) which means imatinib does not bind Role of other enzymes

Answer 14

It a bigger amino acid and interacts with residues in the protein which would normally interact with imatinib. Thus imatinib can no longer bind but ATP still can get in

Answer 15

Less specific kinase blockers whic act on multiplekinases e.g. Pronatinib Other kinases effected include Src

Answer 16

Non steric clash with I315 and blocks ATP binding site Has relative efficacy cytogenic response in all patients = 54% Cytogenetic responce in those with T315I mutation = 70%

Answer 17

Less specificity = more ADRs | Abdo pain, N+V, infections, fever, myalgia

Answer 18

P53 mutations This is a tumour suppressor gene which is stabilised by DNA damage and promotes cell division arrest and apoptosis if defective DNA is detected

Answer 19

Blast crisis and cell is resistant to apoptosis

Answer 20

Gastrointestinal stromal tumours caused by c-Kit mutation (RTK for stem cell factor) which arise from the intestinal cells of cajal Glioblastomas which have PDGF-R mutation Other leukaemias with constitutively active fusion proteins (Tel-PDGF-R)

Answer 21

60% in phase 1 clinical trials

Answer 22

RNAi GPCR antibodies Gene therapy

Answer 23

Give small interfereing RNA (siRNA) or microRNA (double stranded). This binds to dicer which breaks them down into small 21 base long sections. These then bind to argonaut which selects a single strand (guide strand). Complex formed = RNA induced silencing complex. The RISC binds specifically to mRNA of interest via base pair complementation and causes cleavage of mRNA which is degraded by ribonucleases

Answer 24

SiRNA complementary for mRNA which forms Bcr=Abl

Answer 25

Antibody to CCR5 GPCR | Prevent internalisation of HIV