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Importance of Kinases and Deciphera’s Switch Pocket Inhibitors

Kinases play an integral role in maintaining healthy cellular functions and regulating the communication of cells with their environments. However, when kinase mutations occur, cells can lose the ability to normally function and communicate. In many cases, these kinase mutations cause cancer by forcing kinases to adopt active shapes (conformations) independent of normal regulatory processes. This is called conformational escape, because these cancer-causing kinases escape the process of normal regulation.

Many marketed kinase inhibitor drugs are ineffective against such kinase mutations because they are not able to block the aggressive kinase activity. Deciphera’s Switch Pocket Inhibitors retain potency for these aggressive kinase mutants, providing more durable therapies in oncology. Of particular concern is the emergence of the so-called "gatekeeper" mutation. This particular type of aggressive kinase mutation is resistant to all currently marketed therapies. Deciphera's drug candidates retain effectiveness against these gatekeeper mutations.

http://www.deciphera.com/drugs/dcc-2036-cml

The oncogenic fusion protein kinase BCR-ABL causes Philadelphia positive chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL). DCC-2036 is a potent inhibitor of the T315I gatekeeper mutant form of BCR-ABL as well as wild-type and other BCR-ABL variants. The T315I mutant BCR-ABL is resistant to all currently marketed drugs and continues to grow in clinical significance. In a phase 1 clinical trial, DCC-2036 is currently being evaluated in CML patient populations resistant or intolerant to imatinib, nilotinib or dasatinib.

Preclinical evaluations of DCC-2036 demonstrated effectiveness in CML cellular studies and in animal models of human CML. Significantly, DCC-2036 demonstrated superior efficacy over all currently marketed drugs in animal models of highly drug-resistant T315I mutant CML. These results were published in the journal Cancer Cell (Vol. 19: 556, 2011). DCC-2036 also potently inhibits FLT3-ITD, TRKA, and TIE2 kinases implicated in AML, and has demonstrated effectiveness in AML cellular studies.

The phase 1 clinical trial is currently open at four investigator sites: M.D. Anderson, Tufts, the University of Michigan and the University of Kansas. Proof of concept inhibition of T315I BCR-ABL and CrkL signaling have been achieved in CML patients, as well as initial demonstration of hematological, molecular and cytogenetic responses. DCC-2036 is also being evaluated in refractory AML patents. Transition to formulated tablets has been completed to support recommended phase 2 dose selection, and for use in an anticipated 2012 phase 2 trial.

• Information regarding this clinical trial may be found at www.clinicaltrials.gov.