crizotinib   Click here for help

GtoPdb Ligand ID: 4903

Synonyms: (R)-crizotinib | PF 2341066 | PF-02341066 | PF-2341066 | PF2341066 | Xalkori®
Approved drug PDB Ligand Immunopharmacology Ligand
crizotinib is an approved drug (FDA (2011), EMA (2012))
Compound class: Synthetic organic
Comment: Critzotinib is a Type-1 kinase inhibitor and was first approved by the FDA in 2011. It inhibits ALK, cMET and ROS1 receptor tyrosine kinases. Critzotinib is a chiral molecule that exploits the three-dimensional space of the ATP pocket to achieve optimal potency and selectivity [6]. The R-enantiomer as shown here exhibits better potency than the either the racemate or S-isomer and the approved drug should contain only the R-enantiomer.
Pfizer developed the 3rd generation ALK inhibitor lorlatinib as a follow-up to critzotinib, and this new drug has been reported to outperfom its predecessor in lung cancer.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 4
Hydrogen bond donors 2
Rotatable bonds 5
Topological polar surface area 77.99
Molecular weight 449.12
XLogP 4.83
No. Lipinski's rules broken 0
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Canonical SMILES Nc1ncc(cc1OC(c1c(Cl)ccc(c1Cl)F)C)c1cnn(c1)C1CCNCC1
Isomeric SMILES Nc1ncc(cc1O[C@@H](c1c(Cl)ccc(c1Cl)F)C)c1cnn(c1)C1CCNCC1
InChI InChI=1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1
Bioactivity Comments
The (S)-enantiomer ((S)-crizotinib) is considerably less potent than the (R)-enantiomer against its established protein kinase targets [4]. Interestingly, (S)-crizotinib has been reported to inhibit the activity of NUDT1 (P36639) with a Kd of 48nM [4]. NUDT1 is an antimutagenic enzyme involved in the effective elimination of oxidised nucleotides (induced by oxidative stress, for example), thus preventing their incorporation into DNA. At this target the (R)-enantiomer is the less potent enantiomer (Kd 781nM). This highlights the necessity that drug compounds be steroespecifically pure when there is a pharmacological difference in activity between stereoisomers (ie they exhibit distinct molecular mechanisms of action), as enantiomerically impure mixtures may result in off-target effects.
A number of chemical suppliers and other submitters to online chemistry databases specify the non-stereoisomeric molecule depicted in PubChem CID 11597571.
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
MET proto-oncogene, receptor tyrosine kinase Hs Inhibitor Inhibition 8.7 pKi - 1
pKi 8.7 (Ki 2x10-9 M) [1]
MET proto-oncogene, receptor tyrosine kinase Hs Inhibitor Inhibition 9.1 pIC50 - 7
pIC50 9.1 (IC50 7.8x10-10 M) [7]
ALK receptor tyrosine kinase Primary target of this compound Hs Inhibitor Inhibition 9.0 pIC50 - 1
pIC50 9.0 (IC50 1x10-9 M) [1]
Targets where the ligand is described in the comment field
Target Comment
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