Deciphera Pharmaceuticals : BRAF Development Program

Deciphera has recently applied its unique approach to kinase inhibitor design to BRAF kinase. It has been reported that BRAF kinase is one of the most frequently mutated members of the kinase family across all cancers, and is particularly common in malignant melanomas, colon, and thyroid cancers. The V600E mutant form of BRAF kinase in particular represents an activating, dysregulated mutation of BRAF which has been routinely found in cancers.

Deciphera is pursuing two distinct strategies centered on BRAF inhibition. The first strategy seeks potent and highly selective BRAF inhibitors. The second strategy pursues BRAF inhibitors which also inhibit other kinases of interest for broader clinical scope and application. Some representative examples:

DP-2743, DP-2854, and DP-2874 are potent and highly selective inhibitors of BRAF, V600E mutant BRAF, and CRAF. Relative to Nexavar (sorafenib), Deciphera's switch inhibitors are substantially more potent inhibitors of all three RAF enzymes. Unlike Nexavar, which is highly potent against the angiogenic kinases KDR, PDGFR-alpha and PDGFR-beta, Deciphera's compounds substantially avoid these and other kinases, inferring the potential for a superior safety and tolerability profile in chronic management of BRAF dependent cancers. Deciphera's compounds are highly effective as inhibitors of proliferation of BRAF driven tumor cell lines, and potently inhibit the growth of A375 melanoma cells in a mouse xenograft study.

DP-2514 and DP-2473 represent a class of switch pocket inhibitors which combine BRAF activity along with potent inhibition of FLT3, KDR, PDGFR-alpha and PDGFR-beta. This strategy is predicated on the potential for greater efficacy against a broader range of solid tumors where BRAF inhibition alone may be less effective.

Evaluation of BRAF inhibitors in xenograft models

Activity of DP-2514, DP-2473 (Multi-kinase inhibitors) and DP-2743 (Selective RAF inhibitor)
in a mouse A375 xenograft model with oral daily administration, showing inhibition of tumor growth.
Treatment was initiated 7 days after tumor implant.

In vivo inhibition of pMEK and pERK

Western blot showing complete suppression of the RAF-MEK-ERK
signaling pathway by DP-2514 treatment in tumors collected on day 21
of the experiment illustrated above.

Deciphera's RAF inhibitors show no effect on body weight

DP-2514 administered for 14 days shows no change in body
weight compared to vehicle treated mice

Deciphera's BRAF switch pocket inhibitors have thus far demonstrated superior potency and selectivity when compared with competitor agents, as well as excellent safety and pharmacokinetic profiles.

Unique Feature of Switch Inhibitor Kinases: Resistance to so-called "Gatekeeper" Mutations

Among the most common causes of resistance to kinase inhibitor therapy has been the appearance of mutations in the gatekeeper region of the kinase substrate binding domain. Examples of clinically resistant gatekeeper mutations are the T315I form of BCR-ABL, the T790M mutant form of HER1, and the T670I form of KIT. Deciphera has expressed the T529I mutant form of V600E BRAF, which we anticipate to be a likely gatekeeper mutant of the oncogenic kinase, and demonstrated that switch pocket inhibitors retain high potency against this double mutant.

The Deciphera BRAF program is expected to nominate a preclinical development candidate in 3Q 2008.

Deciphera's BRAF Programs: Selective and multi-targeted inhibitors

Two unique programs:

Evaluation of BRAF inhibitors in xenograft models

In vivo inhibition of pMEK and pERK

Deciphera's RAF inhibitors show no effect on body weight

Unique Feature of Switch Inhibitor Kinases: Resistance to so-called "Gatekeeper" Mutations

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