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Switch Pocket Kinase Inhibitors

GIST Support International posed questions about a new type of drug called switch pocket kinase inhibitors to Bryan D. Smith and Scott C. Wise of Deciphera Pharmaceuticals LLC, in Lawrence, Kansas.

Scott C. Wise, M.S. is Director of Biology at Deciphera Pharmaceuticals. He has over 16 years of drug discovery experience ranging from target identification and assay development to in vivo pharmacology and biomarkers. Prior to joining Deciphera he was a Senior Scientist at Pfizer where he worked on numerous discovery projects and played a key role in the implementation of a fully automated miniaturized screening platform capable of processing 500,000 wells/day. Scott also spent time at the National Cancer Institute where he focused on molecular mechanisms of breast and ovarian cancers. He received his Masters degree in Molecular and Cellular Biology from the University of Toledo.

Bryan D. Smith, Ph.D. is a Senior Scientist at Deciphera Pharmaceuticals.  Since starting at Deciphera in 2006, he has been involved in multiple projects with the goal of discovering and developing kinase inhibitors for the treatment of cancer and autoimmune disorders.  Prior to joining Deciphera, Bryan obtained a Ph.D. in Biochemistry at the University of Wisconsin-Madison and a B.S. in Biochemistry from the University of Nebraska-Lincoln.

 

Below are the answers of these two drug discovery scientists to our questions.

1)  In general terms, how do drugs interact with a protein?  What is meant by protein structure?  

Similar to how a key fits in a unique lock, in general a drug has a specific shape and chemical characteristics, including charge, that are complementary to a unique protein.  This complementarity allows for a strong binding interaction between the drug and the protein.  A drug can inhibit or enhance a protein’s activity in order to achieve a therapeutic result. Protein structure refers to the three-dimensional shape of a protein.  Proteins often have several domains that perform different functions.  For example, a precise orientation of chemical groups in the catalytic domain of a protein allows it to perform a specific chemical reaction.  A protein that performs chemical reactions is referred to as an “enzyme.”

2)  What is the catalytic pocket of an enzyme?

The catalytic pocket of the enzyme is where specific chemical reactions take place.  It is referred to as a “pocket” because it is generally an open area inside the enzyme that is accessible from the outside of the enzyme.  Specific molecules can enter and bind into the catalytic pocket.  Enzymes greatly enhance the rate of chemical reactions by binding these molecules in specific orientations.  Drugs can be designed to bind into the catalytic pocket or near to the catalytic pocket to inhibit or enhance the enzyme’s activity.  Kinases are a specific class of enzymes that transfer a phosphate group from ATP to another molecule.  KIT and PDGFRα are called “protein kinases” because they transfer a phosphate group from ATP onto another protein.

3)  How do traditional TKIs such as imatinib and sunitinib bind to KIT or PDGFRα? 

Kinases such as KIT and PDGFRα can be thought of as having “on” and “off” conformations.  In normal cells, KIT or PDGFRα activity is tightly controlled such that the kinase is only turned “on” when needed for normal cellular functions.  When KIT or PDGFRα is mutated in GIST, it is more difficult or even impossible for the cell to turn the kinase “off,” leading to uncontrollable cell growth.  Imatinib and sunitinib were designed to bind into the catalytic pocket or “ATP pocket” of specific kinases.  When imatinib and sunitinib bind to KIT or PDGFRα, they stabilize the kinase in an “off” conformation, therefore blocking kinase activity and stopping growth of cancer cells that require these kinases to be “on”.

4)  What are acquired secondary mutations in KIT, and how do they affect the binding of imatinib, sunitinib and other TKIs to the catalytic pocket? 

Secondary mutations are a major cause of drug resistance.  A primary mutation in KIT causes the kinase to have uncontrolled activity, which can lead to uncontrollable cell growth and cancer.  Cancer cells in general have a higher rate of mutation than normal cells, and secondary mutations in KIT naturally arise during cell growth and division.  In the presence of a drug that is targeted to bind KIT and kill GIST cells, sometimes a secondary mutation occurs that prevents the drug from working and allows a cancer cell to avoid cell death. This resistant cell can then divide uncontrollably, which leads to drug-resistant tumor growth.

Secondary mutations often directly prevent a drug from binding to a kinase by altering the protein structure where the drug binds. Secondary mutations can also have more subtle effects such as  changing the conformation of a kinase such that the drug cannot bind to the altered conformation. 

5)  What is the switch pocket in KIT’s structure and what is its normal function? 

The “switch pocket” is an area on KIT and other kinases that is adjacent to the ATP pocket. The “switch pocket” binds to the activation loop which acts as the major “on-off switch” of a kinase.  The kinase will be active or "on" when the “activation loop switch” is bound to the “switch pocket”.  By preventing the “switch” from binding to the “switch pocket,” a switch pocket inhibitor can prevent a kinase from turning “on” or can even turn “off” an already active kinase.  This approach is complementary to more traditional tyrosine kinase inhibitors that bind to the ATP-pocket of a kinase.  Switch control pockets are different among kinases. These differences provide the opportunity to design drug candidates with unprecedented and unique selectivity profiles.  Blocking the switch pockets with novel drug candidates has resulted in a pipeline of novel therapeutic agents against leukemias, invasive cancers, melanoma, gastrointestinal stromal tumors, bone metastases, and autoimmune diseases. 

 
6) How might switch pocket inhibitors circumvent acquired secondary mutations in the catalytic pocket of resistant GIST?  Would switch pocket inhibitors be susceptible to mutations of the switch pocket?

Since switch pocket inhibitors can force an activated kinase into an “off” conformation, they can inhibit drug-resistant active kinases including secondary mutations in KIT and PDGFRα.  In theory, mutations of the switch pocket could prevent binding of switch pocket inhibitors. However, because an intact switch pocket is necessary to allow the kinase switch to bind in an “on” conformation and allow for kinase activity, they may be less likely to occur.

Deciphera Pharmaceuticals’ switch-pocket inhibitor (DCC-2036) of BCR-ABL kinase for treatment of resistant chronic myelogenous leukemia was tested in a mutagenesis screen for drug resistance.  Mutations were not observed within the switch pocket that prevented inhibition by DCC-2036.  In addition, we have also generated specific mutations in key parts of the switch pocket and found that these mutations result in inactive kinases, which could not lead to resistance.  We have not yet tested this for KIT or PDGFRα with DCC-2618, Deciphera’s drug in preclinical development for GIST.

7)  What is the status of development for switch pocket inhibitors for GIST and for other cancers?  Are there any indications of whether these drugs may cause significant side effects? 

Deciphera’s drug candidate for activated KIT and PDGFRα kinases in GIST is in preclinical development, with the goal of initiating a human clinical trial in the third quarter of 2012.  Side effects will be determined in the clinical trial.  Deciphera currently has a drug, DCC-2036, in clinical trials for chronic myelogenous leukemia, a disease caused by an activated BCR-ABL kinase.  Deciphera also has drugs in preclinical development for solid tumors and highly invasive metastatic cancers that rely on MET kinase activity, tumors that metastasize to the bone that require FMS kinase activity, and for rheumatoid arthritis and autoimmune disorders that rely on FMS kinase activity.  Please see http://www.deciphera.com/drug-pipeline for more information.


 



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