Discovery of a Potent Allosteric Kinase Modulator by Combining Computational and Synthetic Methods

Abstract

The rational design of allosteric kinase modulators is challenging but rewarding. The protein kinase PDK1, which lies at the center of the growth-factor signaling pathway, possesses an allosteric regulatory site previously validated both in vitro and in cells.ANCHOR.QUERYsoftware was used to discover ap otent allosteric PDK1 kinase modulator.U sing ar ecently published PDK1 compound as at emplate,s everal new scaffolds that bind to the allosteric target site were generated and one example was validated. The inhibitor can be synthesized in one step by multicomponent reaction (MCR) chemistry when using the ANCHOR.QUERYapproach.O ur results are significant because the outlined approach allows rapid and efficient scaffold hopping from knownm olecules into new easily accessible and biologically active ones.B ased on increasing interest in allosteric-site drug discovery,w e foresee many potential applications for this approach.Compounds with an allosteric mode of action enable modulation of the protein function that cannot be accomplished by active-site inhibitors. [1] Additionally,a llosteric receptor sites are often less conserved than active sites in ap rotein family.H ence,m ore selective receptor modulation is possible and often new therapeutic qualities can be accomplished. Fore xample,m ost ATP-competitive kinase inhibitors show limited selectivity,a nd therefore clean and selective regulation of acellular pathway is often prohibited. While nonselective kinase inhibitors were considered advantageous for targeting more than one signaling pathway in cancer, some clinical kinase inhibitors show considerable toxicity owing to polypharmacology.M ore-selective kinase inhibitors are potentially better suited for combination with other selective targeted drugs in future personalized treatments.Asasubgroup of the human kinome,the AGCkinases provide au nique opportunity to discover allosteric modulators since ar egulatory allosteric site,t he so called PIFpocket, is well established. [2] Amongst these kinases,3phosphoinositide-dependent protein kinase-1 (PDK1

AnchorQuery: Rapid online virtual screening for small‐molecule protein–protein interaction inhibitors

“…As measured by Google Analytics, in the 12 months from June 2016 to June 2017, more than 1100 users engaged in more than 1800 interactive sessions with more than 400 sessions lasting longer than 3 min. Importantly, AnchorQuery was used as part of the development of novel p53/MDM2 inhibitors and an allosteric PDK1 modulator . We believe that AnchorQuery is a powerful tool for targeting protein–protein interactions using structure‐based design and novel chemistry.…”

“…As an example, in Figure , the compounds generated using the van Leusen reaction were enriched in the results by a factor of 8.3, which is highly significant. This allows chemists to prioritize scaffolds for first synthesis . All result compounds from this reaction are shown (and can be interactively viewed) along with aggregate (min, average, and max) statistics for the enrichment of their starting materials.…”

Allosteric Targeting of Aurora A Kinase Using Small Molecules: A Step Forward Towards Next Generation Medicines?

“…Fragment-based approaches using X-ray crystallography [29] and tethering are more rational ways to identify allosteric ligands. 3-phosphoinositidedependent protein kinase-1 (PDK1) has been subjected to allosteric inhibition by using disulfide-based tethering approach [30]. Recently, computational method [30], vibrational spectroscopic technique (discussed in 1.2.2), etc.…”

“…3-phosphoinositidedependent protein kinase-1 (PDK1) has been subjected to allosteric inhibition by using disulfide-based tethering approach [30]. Recently, computational method [30], vibrational spectroscopic technique (discussed in 1.2.2), etc. to identify distant allosteric sites are also beginning to appear.…”

Novel Compounds Targeting the RNA-Binding Protein HuR. Structure-Based Design, Synthesis, and Interaction Studies

“…Thus, compound 1 was synthesized by a Castagnoli− Cushman reaction (CC-3CR) 25 followed by amidation; 2 by a Groebke−Blackburn−Bienaymé(GBB-2CR); 26 3 by a Van Leusen reaction (vL-3CR), 27 and 4 by a reductive amination 28 followed by acylation. Herein, we will briefly describe the synthetic strategies adopted to obtain compounds 1−4.…”