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Introduction

(Laura)

-Alectinib is an inhibitor of oncogenic c-ros oncogene1 (ROS1) fusion kinases as well as anaplastic lymphoma kinase (ALK). (insert green scene of protein bound to ligand, linking on the word Inhibitor)

-It is a second generation drug that differs from the kinase inhibitor drugs preceding it, in that it's aim is to fight resistance to the inhibitor drugs that occur through mutations (key features/what makes it different)

-This inhibiting complex is likely to be effective in non-small cell lung cancer and other ROS1 fusion-positive cancers

- It is an ATP-competitve inhibitor

-Having difficulties inserting new scene

Overall Structure

Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor with a 5H-benzo[b]carbazol-11(6H)-one structural scaffold ^[2]. (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. ^[3]

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 Interactions

c. The 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 Features

d. PF-06463922 is a novel compound with high affinity for ROS1 and ALK kinases. PF-06463922 is a small molecule that is orally available, ATP-competitive and is CNS-penetrant. PF-06463922 exhibits cellular potency against oncogenic ROS1 fusions and inhibits the crizotinib-resistant mutant ROS1. Compared with crizotinib and the second-generation ROS1 inhibitors ceritinib and alectinib, PF-06463922 exhibits significantly improved inhibitory activity against ROS1 kinase. 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 superior potency of PF-06463922 against ROS1 is due to the multiple interactions between the compound and the ROS1 kinase domain. The aminopyridine core of PF-06463922 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, the study conducted 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 1

e. Quiz question Pose an interesting, quiz-worthy question that involves thinking and investigating the molecule with the green scenes that you provide here. Submit the answer to your question in Moodle and do not share it with other students. Best questions will be chosen for a Moodle quiz, so that students can explore your structure and green scenes to figure out the answer to your quiz question.

See Also

[Structure of Human ROS1 Kinase Domain in Complex]

[Tyrosine kinase]

Credits

Introduction - Laura Feeley

Overall Structure - Katie Kwan

Drug Binding Site - Luke Ruksnaitis

Additional Features - Rafiyu Ishtiaq

Quiz Question 1 - Daniel Peters

References

1. ↑ Zou HY, Li Q, Engstrom LD, West M, Appleman V, Wong KA, McTigue M, Deng YL, Liu W, Brooun A, Timofeevski S, McDonnell SR, Jiang P, Falk MD, Lappin PB, Affolter T, Nichols T, Hu W, Lam J, Johnson TW, Smeal T, Charest A, Fantin VR. PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. Proc Natl Acad Sci U S A. 2015 Mar 2. pii: 201420785. PMID:25733882 doi:http://dx.doi.org/10.1073/pnas.1420785112
2. ↑ Song Z, Wang M, Zhang A. Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance. Acta Pharm Sin B. 2015 Jan;5(1):34-7. doi: 10.1016/j.apsb.2014.12.007. Epub 2015 , Jan 24. PMID:26579422 doi:http://dx.doi.org/10.1016/j.apsb.2014.12.007
3. ↑ Roskoski R Jr. Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition. Pharmacol Res. 2013 Feb;68(1):68-94. doi: 10.1016/j.phrs.2012.11.007. Epub 2012, Nov 28. PMID:23201355 doi:http://dx.doi.org/10.1016/j.phrs.2012.11.007