Deciphera's Phylomechanics Platform
Phylomechanics, Deciphera’s proprietary approach to kinase inhibitor discovery, takes advantage of the most common mechanism for regulation of kinase function. Most kinases are subject to tight regulation through an internal conformational change controlled by facile phosphorylation and dephosphorylation events. Kinase activation results when a phosphorylated loop on the enzyme collapses into a specific binding domain which we refer to as the switch pocket. It is this region of the kinase that Deciphera’s strategy exploits for the design of mechanistically novel inhibitors.
A full motion video clip of the conformational dynamics of kinase activation and inactivation can be viewed by clicking here.
By preventing the binding of the phosphorylated switch loop to its switch pocket, Deciphera’s inhibitors prevent activation of the kinase and also block the ability of activated kinases to associate with other proteins. We believe that by blocking the ability of kinases to nucleate into signaling complexes Deciphera inhibitors may also block alternative signaling mechanisms of kinases which do not depend on their main enzymatic action.
Phylomechanics relies heavily on the application of structure based design technologies. Application of Phylomechanics has been enabled by the discovery of LIBRA, our proprietary protein isolation and crystallization technology. LIBRA has been successfully applied to notoriously difficult kinase targets such as BRAF with the result that Deciphera has achieved multiple co-crystal structures in just a few months.
Switch Inhibitor approach is general
Utilizing its Phylomechanics technology, in just over three years Deciphera identified small molecule leads for over fifty (50) kinase targets, several of which have been further developed to yield potent and highly selective small molecule inhibitors. Close attention has been paid to the physicochemical and pharmaceutical properties of our inhibitors, with the assurance that our inhibitors are both novel and “druggable.”
Targeting oncogenic kinase switches
It is now well established that point mutations, sequence deletions, or amino acid residue insertions within the kinase switching mechanism can lead to unregulated kinase activity which is the basis for many cancers. 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, while sparing normal BRAF
- Inhibition of the oncogenic Internal Tandem Repeat (ITR) variant of FLT3 kinase
- Inhibition of the activating L858R mutant of HER1 (EGFR) kinase
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.
Because switch pocket inhibitors inhibit kinases by a totally unique mechanism, Deciphera’s inhibitors retain full potency against known gatekeeper mutations such as the T315I mutant form of BCR-ABL.
Switch pocket inhibitors provide unique kinase selectivity profiles
Most kinase inhibitor strategies focus on the ATP binding domain, 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 the main challenge for this very reason.
In contrast, the switch pocket structure is quite unique for a given kinase, since each switch pocket is intended to bind a unique peptide sequence comprising the kinase switch loop. Deciphera’s Phylomechanics approach takes advantage of the structural diversity of switch pockets with the result that inhibitors have been identified with unprecedented selectivity profiles.
The unique features of each kinase switch pocket also enable the opportunity to rationally design compounds which can selectively target a selected subset of kinases. Since the most effective therapeutic profile for treatment of some cancers may require the simultaneous inhibition of two or more kinases, this ability to customize the profile of inhibition through the Deciphera Phylomechanics approach enables very unique ensemble strategies. Some examples of strategies now being pursued include HER2/MET, combined BRAF/angiogenic kinase targets inhibition, and ensemble strategies for both our JAK2 and AXL programs.
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eciphera has developed a suite of proprietary technologies for probing switch mechanisms in kinases, which control their shapes and biological activities. 
