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Protein complex with cancer drug Alecensa-Alectinib (4uxl)[1]
by Laura Feeley, Katie Kwan, Daniel Peters, Ishtiaq Rafiyu, Luke Ruksnaitis
Student Projects for UMass Chemistry 423 Spring 2016
Introduction, otherwise known as Alecensa, is an FDA approved second generation drug that is used to primarily target non-small-cell lung cancer. It functions as an anaplastic lymphoma kinase(ALK) and Oncogenic c-ros oncogene1 (ROS1) fusion kinase inhibitor. Alectinib was approved by the FDA for immediate release in December of 2015. It is prescribed when anaplastic lymphoma kinase gene mutations occur as a response to the first generation drug, crizotinib, and pose a risk of spreading to the brain. Alectinib inhibits the gatekeeper L1196M mutation that occurs in response to crizotinib.[2] The ligand (in green) for the ROS1 kinase complex was found to be (10R)-7-amino-12-fluoro-2,10,16-trimethyl- 15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3- h][2,5,11]benzoxadiazacyclotetradecine-3- carbonitrile, although identifying ligands for receptor ALK is a topic of on going research.[3] The bound complex aims to inhibit pathways that are activated through phosphorylation, and in turn stop uncontrolled growth of the point mutations created from a resistance to crizotinib. Alectinib is utilized in patients when the first generation drug, crizotinib, also an anaplastic lymphoma kinase inhibitor, has failed to work. Crizotinib did have a sixty percent tumor response but the side effects included diarrhea, nausea, vomiting, and constipation.[4]. Alectitinib aims to have a successful inhibitory response but also to reduce the magnitude of these side effects. The success of alectinib is the result of its effectiveness against the mutations created in response to the first generation drug crizotinib. In the two clinical trials that have been conducted, there were tumor reductions in thirty-eight percent of patients which then increased to forty-four percent in the second trial. It was found in a trial of patients with brain metastases that sixty percent had a complete or partial reduction of tumors.
Overall StructureAlectinib is an anaplastic lymphoma kinase (ALK) inhibitor with a 5H-benzo[b]carbazol-11(6H)-one structural scaffold [5]. (chemical name: 9-Ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo- 6, 11-dihydro-5H-benzo[b]carbazole-3carbonitrile hydrochloride) The consists of a small N-terminus lobe and a large C-terminus lobe. The N-terminus lobe holds a 5-stranded antiparallel β sheet, and a αC helix. The C-terminus lobe contains a glycine rich ATP binding loop, located between the first and second β strands. This large lobe mostly contains α helices (six conserved segments), and two short β strands. [6] The structure also contains four hydrophobic residues that form the regulatory spine, and eight hydrophobic residues that form the catalytic spine. Hydrophobic and Polar, regions of the ALK inhibitor can be seen . Binding InteractionsThe binding interaction of PF-0643922 with ROS1/ALK is what makes Alectinib a second generation drug. Patients developed resistance to the first generation drug crizotinib by developing point mutations in the ROS1 kinase. PF-0643922 is a very strong potent and selective small molecule inhibitor that targets the (ROS1) fusion kinase. Inhibition of the fusion kinase is the goal of this cancer therapy. PF-0643922 is the most potent and selective ROS1 inhibitor discovered to date according to the paper cited. PF-0643922 is the small molecule of the protein complex of ROS1 inhibitors that gets the job done on its own compared to alectinib and crizotinib. Alectinib's goal is to fight resistance to the inhibition of ROS1 kinase through selectively binding to the point mutations. However PF-0643922 has been shown to inhibit the crizotinib-refractory ROS1(G2032R) mutation and the ROS1(G2026M) gatekeeper mutation which would ultimately make crizotinib and alectinib obsolete ROS1 inhibitors. The crystal structure between the PF-0643922-ROS1 complex shows the interactions that contribute to the high affinity binding of PF-0643922. The first blue dot alone by itself is the N terminus, and the three carbon atoms next to the nitrogen and oxygen is the C terminus. The binding site of the protein complex is therefor the cluster of atoms with the green dot.
Additional FeaturesPF-06463922 is a compound with high affinity for ROS1 and ALK kinases. PF-06463922 is a small molecule that is orally available, ATP-competitive and can penetrate CNS. PF-06463922 exhibits cellular potency against oncogenic ROS1 fusions and inhibits the crizotinib-resistant mutant ROS1. When compared with crizotinib and the second-generation ROS1 inhibitors such as ceritinib and alectinib, PF-06463922 exhibits significantly improved inhibitory activity against ROS1 kinase. Recent studies have shown that when compared with other kinase inhibitors, PF-06463922 is 10-times more potent than crizotinib and foretinib and 100-fold more potent than either ceritinib or alectinib in both ROS1 cell growth and ROS1 kinase inhibition. PF-06463922 makes many favorable interactions with ROS1. Co-crystal structure analysis revealed that the high potency of PF-06463922 against ROS1 is due to the multiple interactions between the compound and the ROS1 kinase domain. The PF-06463922 has an aminopyridine core that makes two hydrogen bonds to the kinase hinge segment thus creating a stable complex. To investigate the PK/PD relationship between PF-06463922 plasma concentration and inhibition of tumor growth, recent conducted study showed that a direct-response modeling analysis in the NIH 3T3 FIG-ROS1 model. Their Hill equation analysis showed a reasonable fit of R2 = 0.79, and the estimated concentrations used, PF-06463922 were 5.8 nM for tumor stasis and 9 nM for 30% tumor regression of FIG-ROS1 s.c. tumors. Tyrosine kinase inhibitors for protein tyrosine kinase (ALK/LTK) and insulin receptor are phylogenetically related to the anaplastic lymphoma kinase/lymphocyte and suggests that they could have cross-activity against ROS1.
Quiz Question 1Quiz question Using the inhibiting complex scene given below where is the binding site located?
red:Oxygen blue:Nitrogen green:Florine A)At the nitrogen atom after the alpha helix B)At the nitrogen to oxygen complex C)At the oxygen/nitrogen complex that contains a florine atom D)all of the above
See Also[Structure of Human ROS1 Kinase Domain in Complex] CreditsIntroduction - Laura Feeley Overall Structure - Katie Kwan Drug Binding Site - Luke Ruksnaitis Additional Features - Rafiyu Ishtiaq Quiz Question 1 - Daniel Peters References
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