Deciphera's Platform

Controlling Kinase Shape Deciphera's approach to kinase inhibition takes advantage of the natural mechanism of kinase regulation. Most kinases are tightly regulated by an internal conformational (shape) change controlled by phosphorylation and dephosphorylation of key kinase regions which we refer to as the kinase switch. Kinase activation results when a phosphorylated switch binds into a complementary region which we refer to as the switch pocket. The switch pocket is the region that Deciphera exploits for the design of novel inhibitors. Deciphera's inhibitors block conformational activation of kinases, preventing the binding of the phosphorylated switch to its pocket.

Switch Inhibition of kinases is general. Deciphera has identified small molecule leads for over fifty (50) kinase targets by screening of its proprietary biased chemical library. Close attention has been paid to the physicochemical and pharmaceutical properties of chemotypes, with the assurance that orally bioavailable inhibitors are readily identified. Nine of these screens have produced lead optimization programs, while three programs have been further advanced to yield development candidates.

New therapies in Cancer… targeting oncogenic kinases. It is now well established that amino acid point mutations, sequence deletions, or insertions within the kinase switching mechanism can lead to unregulated kinase activity. Deciphera's switch pocket inhibitor approach has been demonstrated to potently reverse the effects of these cancer-causing mutations. Some specific examples are:

• Inhibition of the oncogenic V600E amino acid mutant of BRAF kinase (malignant melanoma)
• Inhibition of primary (juxtamembrane deletion) and secondary (point mutations) in cKIT kinase, including D816Vand V654A (gastrointestinal stromal tumors)
• Inhibition of the oncogenic Internal Tandem Repeat (ITR) variant of FLT3 kinase (acute myeloid leukemia)
• Inhibition of the activating L858R mutant of HER1 kinase (breast cancer, lung cancer)

Targeting gatekeeper kinase mutations A distinguishing feature of switch pocket inhibitors is their high potency for so-called gatekeeper mutations of kinases. The gatekeeper residue is located next to the ATP binding region, and is susceptible to mutational changes. Nearly all ATP clinically used kinase inhibitors lose potency when the gatekeeper mutations occur, resulting in loss of efficacy. Deciphera's inhibitors retain full potency against known gatekeeper mutations such as T315I mutant BCR-ABL, T529I B-Raf, and T670I cKIT.

Switch pocket inhibitors provide unique kinase selectivity profiles
Most kinase inhibitor strategies focus on the ATP binding pocket, which is generally similar across all 518 kinases in the human genome. In most cases, development of an inhibitor which is selective for the intended target has been a major challenge. In contrast, the switch pocket is quite unique for a given kinase or sub-family, since each switch pocket is intended to bind a unique peptide sequence comprising the embedded kinase switch. Deciphera's approach takes advantage of the structural diversity of switch pockets with the result that inhibitors have been identified with unprecedented selectivity profiles.

LIBRA technology for solving kinase XRay structures Deciphera's approach relies significantly on the application of structure based design technologies. Structure-based design has been enabled by the discovery of LIBRA (Ligand Induced Binding to Reduce Aggregation), a proprietary protein purification and crystallization technology that maintains kinases in low aggregation states during isolation and crystallization experiments. LIBRA has been successfully applied to notoriously difficult kinase targets such as B-Raf with the result that Deciphera has achieved multiple co-crystal structures in just a few months.

Deciphera Pharmaceuticals, LLC
643 Massachusetts
Suite 200
Lawrence, KS 66044

785 830-2100 phone
785 830-2150 fax
info@deciphera.com

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