eciphera's kinase switch inhibitors target the mechanisms that render kinases oncogenic, retain potency against gatekeeper mutations, and afford selectivity profiles not easily attained by other approaches.

BCR-ABL Development Summary

BRAF Development Summary

Deciphera's Oncology Programs

Deciphera’s proprietary Phylomechanics approach to kinase inhibitor design has been applied to a number of clinically important kinase targets in the cancer area. In most cases, the result has been the discovery of mechanistically novel inhibitors with superior profiles.

BCR-ABL Program

The BCR-ABL program has produced orally bioavailable switch inhibitors that are 70-100 fold more potent than Gleevec. Deciphera's switch control inhibitors are also highly effective against Gleevec-resistant clinical mutants of BCR-ABL, including the T315I mutant. DCC-2036 is currently in preclinical development for use in the treatment of resistant or intolerant chronic myelogenous leukemia patients.

BRAF Program

Our single digit nanomolar inhibitors of oncogenic BRAF kinase (V600E) exhibit potent inhibition of cellular proliferation in a variety of melanoma and colon cancer cell lines. Outstanding efficacy with Deciphera BRAF switch pocket inhibitors has been demonstrated in mouse A375 xenograft studies, which correlates with complete suppression of ERK phosphorylation in tumors harvested from these experiments. Deciphera's mature BRAF program is poised to advance compounds into preclinical development during Q4 of 2008.

MET/HER solid tumor Program

Deciphera’s multikinase inhibition strategy for the design of broad spectrum treatment of solid tumors encompasses four functionally distinct groups of kinases:

• Mechanisms which drive tumor growth (HER kinases)
• Mechanisms which promote cell survival (CRAF)
• Mechanisms which support metastasis(BRAF, KDR, PDGFR)
• Mechanisms which promote tumor angiogenesis (KDR, PDGFR)

None of the kinase inhibitors currently in clinical use today inhibit all four mechanisms of solid tumor growth and survival, which Deciphera believes to limit their effectiveness. Deciphera has identified several chemical classes of switch pocket inhibitors which meet the desired ensemble profile for a clinically superior agent, and is actively pursuing this exciting program.

KIT Program

Gastrointestinal stromal tumors (GIST) are associated with a gain-of-function mutation of the kinase KIT. The ability of a KIT inhibitor to control this disease has been demonstrated through the BCR-ABL inhibitor Gleevec, although its inhibitory potency against KIT is in the low micromolar range. Recently, the T670I form of KIT was identified which resists inhibition by Gleevec and results in treatment failures in GIST patients bearing this mutation. Deciphera’s early stage KIT program has been highly successful in the discovery of potent switch pocket inhibitors of KIT with retention of potency against the resistant mutant, offering the potential for significant improvement in the management of this disease.

JAK2 Program

Myeloproliferative disorders (MPD) are a subcategory of hematological malignancies characterized by a stem cell-derived clonal proliferation of myeloid cells including erythrocytes, platelets, and leukocytes. Traditionally, the term 'MPD' included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis with myeloid metaplasia (MMM). Recent studies suggest that JAK2 V617F is an acquired myeloid lineage-specific mutation that engenders a pathogenetic relevance for the PV phenotype in MPD. Deciphera's Phylomechanics platform has identified a number of JAK2 switch inhibitor leads as the basis for a new discovery program.

Deciphera Pharmaceuticals, LLC
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info@deciphera.com

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