Crizotinib

On a totally different subject from theatres, I have just graduated with a First Class degree in Chemistry with a dissertation on a novel drug to treat a specific subset of lung cancers, called crizotinib. Whilst the project cannot be published, the abstract is shown below. If it interests you, please contact me!

TITLE

A review of the mechanism, binding, synthesis and future of the anaplastic lymphoma kinase inhibitor drug crizotinib.

ABSTRACT

Crizotinib, 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4- yl)pyridin- 2-amine), is a first-in-class inhibitor of anaplastic lymphoma kinase (ALK) and mesenchymal epithelial transition factor (c-Met). It binds to these receptor tyrosine kinases (RTK) in place of adenosine triphosphate (ATP), preventing subsequent phosphorylation of tyrosine residues and interrupting the cell signalling necessary for cancer cell survival.

It is currently approved only for non-small cell lung cancers (NSCLC) positive for specific ALK translocations. C-Met and proto-oncogene tyrosine-protein kinase ros (ROS1) are under investigation for future treatment, as are other cancers with ALK mutations, including neuroblastoma. Meeting Lipinski’s Rule of Five, crizotinib can be administered orally, resulting in improved quality of life compared to conventional chemotherapy.

A π-π stacking interaction and hydrophobic bonds from the R-methyl create a nano-molar potency with c-Met (IC50=8nM). It shows reduced affinity with ALK due to the lack of π-π stacking and a steric clash (IC50 =20nM). Further mutations such as L1196M reduce this further. A number of synthesis towards the active S-isomer have been published, mostly utilising Mitsunobu and palladium-catalysed Suzuki coupling reactions. Enantioselectivity is achieved by using (1S)-1-(2,6- dichloro-3-fluoro-phenyl)ethanol, formed via novel enzyme- mediated ketoreduction or iridium catalysis utilising Ir[(R)-DTB-SpiroPAP-3-Me].

The opposite S-isomer is found to be an effective inhibitor of human 8-oxo-dGTPase (MTH1), part of a DNA repair mechanism in cancer cells offering a future target. Optimisation through structural modifications has improved ALK binding, creating (2R)-2- [5-[6-amino-5-[(1R)-1-[5-fluoro-2- (triazol-2-yl)phenyl]ethoxy]-3-pyridyl]-4-methyl-2,3- dihydrothiazol-2-yl]propane-1,2-diol. This shows increased bioavailability and potency (IC50=0.8nM). Brain metastases are a common side- effect, initially attributed to poor penetration of crizotinib through the blood-brain barrier (BBB), a ratio of 0.0026 compared to plasma. This is possibly due to efflux by p-gp proteins, and their inhibition via elacridar co- administration can lead to improved outcomes.

Crizotinib shows promise for the future due to its potency across an increasing range of oncogenic targets, desirable oral administration, and opportunities for structural modification and co- administration.

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s