Tinkering Outside the Kinase ATP Box: Allosteric (Type IV) and Bivalent (Type V) Inhibitors of Protein Kinases

Abstract

Many members of the protein kinase family have emerged as key targets for pharmacological intervention, most notably in cancer. However, the high sequence and structural homology shared by the more than 500 human protein kinases renders it exceedingly difficult to develop selective inhibitors. Most, if not all, existing inhibitors target multiple protein kinases. Current paradigm suggests that an inhibitor that targets multiple kinases and displays polypharmacology is not only acceptable but also often desirable as a therapeutic agent. However, as we move toward personalized medicine the currently acceptable promiscuity is likely to pose significant hurdles in terms of their therapeutic index, especially for diseases that necessitate long-term drug administration. Moreover, selective inhibitors are the only pharmacologically relevant route toward reagents for the dissection of complex signal transduction pathways. This article provides an overview of recent developments in the design of kinase inhibitors that display increasing selectivity by targeting regions outside the highly conserved ATP-binding pocket. These new approaches may pave the way to potentially new avenues for drug discovery while providing valuable tools for studying signal transduction.

FDA-approved small-molecule kinase inhibitors

“…In the type III binding mode, inhibitors bind exclusively in an allosteric pocket adjacent to ATP without making any interaction with the ATP-binding pocket. Type IV inhibitors bind to an allosteric site remote from the ATP-binding pocket [25]. Some kinase inhibitors, such as bisubstrate and bivalent inhibitors (type V) [26], exhibit more than one of these binding modes.…”

Small-molecule kinase inhibitors: an analysis of FDA-approved drugs

“…To date, most of the approved SMKIs are ATP competitive inhibitors [17], which include type I inhibitors, which bind with the adenine site of the ATP pocket, with the DFG motif of the activation loop adopting an 'in' conformation, and type II inhibitors, which bind with both the ATP pocket and an adjacent allosteric pocket created as a result of the DFG 'out' conformation. Of the 25 noncovalent ATP competitive SMKIs, lenvatinib showed both type I and type II binding features [18] and, thus, is grouped as a type V inhibitor [19]. Trametinib, which does not bind into the ATP binding pocket, but instead occupies an adjacent allosteric pocket, is the only type III inhibitor approved to date.…”

Double-Edged Sword of the New Cancer Therapeutics

“…Off-target toxicity arises from the inherent lack of selectivity of the vast majority of small-molecule kinase inhibitors. 14,15 That is, one may set out to make a compound targeted at a specific kinase (eg, BCR-Abl) but it is the very rare compound that is truly selective. This is highlighted in Table 5 of Montani et al, which shows the rather promiscuous selectivity profile of dasatinib (with Ͼ40 kinases as possible targets) compared with imatinib and nilotinib, 2 of the most selective agents on the market.…”