Sandbox Reserved 432

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

b. Overall structure (Katie) Describe the overall structure of your protein in words and make "green scenes" to illustrate your points.

What elements of secondary structure are present (ie 5 alpha helices and 2 beta strands) and how are they organized?

-The Human ROS1 Kinase Domain in Complex consists of a small N-terminus lob and a large C-terminus lobe. The N-terminus lobe contains a 5 stranded antiparallel bets sheet and an alpha helix.

-The C-terminus lobe consists mainly of an alpha helix which contains 6 segments, as well as 2 conserved beta strands. This lobe has helical structure and is there the regulatory activation loop is located.

Additional description and green scenes could illustrate the polar/nonpolar distrubution of amino acids (is the inside of the barrel polar or nonpolar?), packing of amphipathic elements, etc.

Ligand 5p8: (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

289 amino acids

Binding Interactions

c. Alectinib is a selective ALK inhibitor. Alectinib has shown to reduce tumor growth in mice. Strong statistics have been shown in tumor regression due to the crystalline structure of alectinib in its interaction with ALK is not retarded by steric hindrance. Due to the nature of tumors being rather knotty and tangled with steric hindrance all around them alectinib's resilience to steric hindrance proves to be a strong antitumor capability. The green scene will show the crystalline structure of alectinib interacting with ALK in comparison to crizotinib with ALK.

Additional Features

d. Additional features Describe and use green scenes to illustrate additional features of the macromolecule. What you do here depends on what information is available. If a structure of the protein-substrate complex is available, you could compare protein interactions with the substrate vs. with the drug. If the drug is a transition state inhibitor, explain and illustrate that (eg include a reaction scheme with structures of the substrate, transition state and product -- but don't borrow a published scheme).

- PF-06463922 is a novel compound with high affinity for ROS1 and ALK kinases 

- PF-06463922 Inhibits Crizotinib-Resistant Mutant ROS1

- PF-06463922 effectively inhibits the catalytic activity of recombinant ROS1

- Compared with other kinase inhibitors, PF-06463922 was >10-fold more potent than crizotinib and foretinib and >100-fold more potent than either ceritinib or alectinib in both ROS1 fusion-mediated cell growth and ROS1 kinase inhibition

- To date, interchromosomal translocations or intrachromosomal deletions have resulted in the production of 20 different N-terminal ROS1 fusion genes in a variety of cancers

- ROS1 is a distinct receptor with a kinase domain that is phylogenetically related to the anaplastic lymphoma kinase/lymphocyte-specific protein tyrosine kinase (ALK/LTK) and insulin receptor (INSR) RTK families (20), suggesting that tyrosine kinase inhibitors for these receptors 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 - name of team member

Quiz Question 1 - name of team member

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