modes of small molecule kinase inhibitor action

Question 1

what are type 1 Kinase inhibitors

Answer 1

Compete with ATP binding site
Broad spectrum and nonselective
risk of side effects is higher
ex: staurospoine

Question 2

what are type 2 kinase inhibitors

Answer 2

bind to atp site but dont compete because they bind to inactive non-phosphorylated form of kinase (DFGout, additional hydrophobic pocket available for binding, can be more selective)
They have higher affinity for non-phosphorylated conformation but still bind to active
ex: imatinib, crizotinib, Lapatinib

Question 3

what are type 3/4 kinase inhibitors

Answer 3

3: Binding site adjacent to ATP
4: binding site distant from ATP site
both are allosteric
This increases selectivity
they can be both noncompetitive (doesnt distinguish between atp bound/unbound kinase) or uncompetitive (inhibitor binding enhanced when ATP present)

Question 4

describe consequences of polypharmacology with kinase inhibitors

Answer 4

ex1: target of imatinib is BCR-Abl
however it also targets PDGFR and KIT
this increases risk of side effects
However kinases often treat cancer and cancers can have overactivity of multiple kinases
Therefore imatinib is useful for GI tumors where PDGFR KIT shows overactivity
ex2: Crizotinib designed to inhibit MET which is expressed in non-small cell lung cancer.
Also inhibits EML4-Alk. its anti cancer effects observed were related to this.
therefore polypharmacology can be useful

Question 5

give an example of a type 3 kinase inhibitor

Answer 5

binimetinib: MEK inhibitor. (involved in MAPkinase signalling pathwa7. Inhbitis upstream pathways in cancer)
has an uncpompetitive mechanism (ATP presence enhances binding)

Question 6

give an example of a type 4 kinase inhibitor

Answer 6

Abl 1b kinase expressed physiologically has N terminal myristoylation (fatty acids added)
this binds to a pocket in the c-lobe which decreases kinase activity
However in chronic myeloid leukemia where BCR is fused with abl there is no myristylation
Asiminib binds to the myristoylate binding pocket on the c lobe e,f,h helix.
asiminib is highly selective and only inhibits BCR-abl and also can persevere its function when bcr-abl mutates

Question 7

give an example of how mutations in cancer can be targeted with kinases.

Answer 7

B raf involved in the MAPK cascade
valine is nonpolar and neutral and. val 600 is replaced by acidic and negatively charged Glutamic acid.
this increases B-raf activity and activates the pro-proliferative MAPkinase pathway

This mutation is present in 50% of melanomas and other cancers.
two kinase inhibitors for the ATP binding site were designed to have higher affinity for the v600e conformation.

ex: vemurafenib and dabrafenib.

experimental evidence showed the selective inhibition of growth in cancer cell lines with v600e
this mutation is example of oncogenic addiction (cell survival dependent on mapkinase pathway which is activated by b raf v600e)

Question 8

what are limitations of targeting cancer mutations with kinases

Answer 8

1. Resistance often develops within 12 months
2. other mutations in cancer can be insensitive to inhibitors (v600e mutation is rare example)
3. paradoxical potentiation. trying to inhibit b-raf activity can lead to more dimerisation of the wild type causing activation of b raf in other cells.