Deciphera Pharmaceuticals : bcr-Abl Program

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.

Deciphera's BCR-ABL Development Program

BCR-ABL inhibitor: DCC-2036

DCC-2036 is a potent BCR-ABL inhibitor now in preclinical development for the management of treatment-resistant or intolerant chronic myeloid leukemia (CML). DCC-2036’s profile is superior to the marketed agents imatinib (Gleevec) and dasatinib (Sprycel) principally with regard to its potency against the clinically important T315I mutant form of BCR-ABL, which is insensitive to either marketed agent. The emergence of resistance to Gleevec as a result of mutational changes in BCR-ABL is developing as a serious challenge in the effective management of CML. This has created an opportunity for the introduction of new agents which retain activity against these mutant forms. By targeting a unique domain on the enzyme for binding and inhibition, DCC-2036 has been shown in various in vitro and in vivo experiments to be a potent and effective inhibitor of treatment resistant mutants, including the T315I mutation which is insensitive to Gleevec and Sprycel. DCC-2036 displays excellent oral biovailability and pharmacokinetics, a remarkably clean off-target profile, and a highly promising profile in safety studies. The table below provides a sampling of the activity profile of DCC-2036 against a range of resistant mutants in a cell proliferation assay.

BCR-ABL Next Generation Inhibitors

Deciphera is continuing to expand upon its portfolio of BDR-ABL switch pocket inhibitors through the design of compounds with even greater potency and which can incorporate potent inhibition of other kinases which we believe would further enhance the clinical utility of a next generation drug candidate. Some examples:

DP-2629, a potent inhibitor of BCR-ABL with even greater selectivity vs. other kinases relative to the flagship compound DCC-2036.

DP-2494, a subnamolar inhibitor of BCR-ABL, which exhibits low nanomolar potency against the T670I mutant form of KIT. This specific KIT mutation confers resistance to treatment by imatinib (Gleevec) of gastrointestinal stromal tumors (GIST).

Deciphera plans to advance a next generation candidate from this program into preclinical development during 2Q 2008.

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