modes of small molecule inhibitors actions -H Flashcards
Type I kinase inhibitors overview and example
Staurosporine (PIM1), axitinib (VEGFR), afatinib (EGFR)
They compete with ATP for the binding site. As such they are quite non-selective. High risk of side effects/toxicity.
Unaffected by conformation of the receptor
Type II kinase inhibitors (bcr and met) mechanisms, examples, limitations, and polypharmacology in cancer
Also bind to the ATP binding site, however only when the DFG motif is in the DFGout conformation (inactive).
In the DFGout conformation there is another hydrophobic pocket available in the binding site, which enables some extra selectivity.
Imatinib is type II (BCR-Abl). More selective, but still has activity at PDGFR and KIT. this polypharmacology has proved useful however. Imatinib also has uses in PDGFR/KIT mediated GI tumours.
Crizotinib is another example, a selective MET inhibitor. Its lack of polypharmacology meant it was less useful for treating NSCLC, as EML4-Alk fusion kinase was more involved.
Alectinib, brigatinib, and lorlatinib were developed for Alk-specificity.
Type III kinase inhibitors mechanisms and examples
Binds to a site adjacent to the ATP binding site. Has better selectivity.
Can have non-competitive or uncompetitive mechanisms of action.
Binimetinib is an uncompetitive MEK inhibitor (involved in MAPK cascade).
Type IV kinase inhibitors mechanisms and examples
Binds to a site far from the ATP binding site. Has improved selectivity and can act non-competitively or uncompetitively.
Physiological Abl 1b has N-terminal myriostoylation (modification of fatty acids). This negatively regulates the kainse catalytic domain by binding to a pocket in the C-lobe. This myistoylate is lost in BCR-Abl, but the binding site remains.
Asiminib is a BCR-Abl inhibitor that is highly selective for this C-lobe binding site (myristolate) and has preserved activity against L5-mutant BCR-Abl.
Targeting BRaf kinase mutation in cancer mechanisms, example and limitations
B-Raf V600E is a mutation in the catalytic domain activation loop. The presence of the acidic, -ve valine leads to constituative activity and activation of the MAPK pathway - proliferative.
It is seen in 50% of melanomas and other cancers such as NSCLC.
Vemurafenib and dabrafenib were designed to have high affinity for the mutated B-Raf ATP binding site. They are called type 1.5 inhibitors (same mechanism as type 1).
There are also other classes of B-Raf seen to be involved in cancer, and these inhibitors have limited effect on them.
These inhibitors have also sometimes been shown to have a paradoxical effect of potentiating WT B-Raf dimerisation, which can lead to other cancer development. Even further worsened if there is activation of Ras-MAPK already.
