Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery

Erlanson, Daniel A.; Arndt, Joseph W.; Cancilla, Mark T.; Cao, Kathy; Elling, R.A.; English, Nicki; Friedman, Jessica; Hansen, Steven G.; Hession, Cathy; Joseph, Ingrid B.J.; Kumaravel, Gnanasambandam; Lee, Wen‐Cherng; Lind, Ken; McDowell, Robert S.; Miatkowski, Konrad; Nguyen, Christine; Nguyen, Thinh B.; Park, Sophia; Pathan, Nuzhat; Penny, David M.; Romanowski, M.J.; Scott, Daniel A.; Silvian, Laura; Simmons, Robert L.; Tangonan, Bradley T.; Yang, Wenjin; Sun, Lihong

doi:10.1016/j.bmcl.2011.03.032

Cited by 77 publications

(43 citation statements)

References 17 publications

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“…Fragments making favorable interactions with protein will form stable disulfide bonds with extender and are detected by mass spectrometry. Recently, Erlanson et al [98] used tethering with extender to identify inhibitors of 3-phosphoinositide dependent protein kinase-1 (PDK1). Another modification to tethering is tethering with dynamic extenders, in which an irreversible electrophile of 'extender' is replaced with disulfide that enables reversible cysteine modification.…”

Section: Tetheringmentioning

confidence: 99%

Fragment Based Drug Design: From Experimental to Computational Approaches

Kumar

Voet²,

Zhang

2012

CMC

146

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Fragment based drug design has emerged as an effective alternative to high throughput screening for the identification of lead compounds in drug discovery in the past fifteen years. Fragment based screening and optimization methods have achieved credible success in many drug discovery projects with one approved drug and many more compounds in clinical trials. The fragment based drug design starts with the identification of fragments or low molecular weight compounds that generally bind with weak affinity to the target of interest. The fragments that form high quality interactions are then optimized to lead compounds with high affinity and selectivity. The weak affinity of fragments for their target requires the use of biophysical techniques such as nuclear magnetic resonance, X-ray crystallography or surface plasmon resonance to identify hits. These techniques are very sensitive and some of them provide detailed protein fragment interaction information that is important for fragment to lead optimization. Despite the huge advances in technology in the past years, experimental methods of fragment screening suffer several challenges such as low throughput, high cost of instruments and experiments, high protein and fragment concentration requirements. To address challenges posed by experimental screening approaches, computational methods were developed that play an important role in fragment library design, fragment screening and optimization of initial fragment hits. The computational approaches of fragment screening and optimization are most useful when they are used in combination with experimental approaches. The use of virtual fragment based screening in combination with experimental methods has fostered the application of fragment based drug design to important biological targets including protein-protein interactions and membrane proteins such as GPCRs. This review provides an overview of experimental and computational screening approaches used in fragment based drug discovery with an emphasis on recent successes achieved in discovering potent lead molecules using these approaches.

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Section: Tetheringmentioning

confidence: 99%

Fragment Based Drug Design: From Experimental to Computational Approaches

Kumar

Voet²,

Zhang

2012

CMC

146

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“…49 This approach resulted in the discovery of a fragment that was subsequently elaborated to generate a highly selective type II PDK1 kinase inhibitor. (50) Another approach reported by Abagyan et al has involved a computational in vitro screen against a model of a DFG-out conformation of the targeted kinase. 32 High-throughput biochemical assays with highly activated recombinant enzymes is the typical approach to discover type I kinase inhibitors and is sometimes biased against type II compounds, which typically preferentially bind to the dephosphorylated, inactive kinase.…”

Section: Strategies To Develop New Type II Kinase Inhibitorsmentioning

confidence: 99%

Exploration of Type II Binding Mode: A Privileged Approach for Kinase Inhibitor Focused Drug Discovery?

et al. 2014

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The ATP site of kinases displays remarkable conformational flexibility when accommodating chemically diverse small molecule inhibitors. The so-called activation segment, whose conformation controls catalytic activity and access to the substrate binding pocket, can undergo a large conformational change with the active state assuming a ‘DFG-in’ and an inactive state assuming a ‘DFG-out’ conformation. Compounds that preferentially bind to the DFG-out conformation are typically called ‘type II’ inhibitors in contrast to ‘type I’ inhibitors that bind to the DFG-in conformation. This review surveys the large number of type II inhibitors that have been developed and provides an analysis of their crystallographically determined binding modes. Using a small library of type II inhibitors, we demonstrate that more than 200 kinases can be targeted, suggesting that type II inhibitors may not be intrinsically more selective than type I inhibitors.

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“…Using the SGX X-ray crystallographic screening protocol, a fragment library designed to have good physical chemical and drug-like properties, yielded several hits. They selected a bromoamino-imidazole to follow-up (41 μM IC 50 ) for a fragment growth Covalent tethering to screen thiol library followed with SBDD optimization [ 82 ] Fragment Based Design of Kinase Inhibitors strategy due to its high LE (0.54) and its potential substitution points. Using the X-ray structure, viable vectors for growth were selected, namely the 5-and 6-positions of the indazole, and several analogs were synthesized.…”

Section: Vbsmentioning

confidence: 99%

“…This is mainly due to the common use of X-ray structural data, where the binding of multiple fragments in the same structure are not as common as single fragment binding. An interesting alternative approach uses a technique of tethering a fragment covalently to the kinase followed by X-ray crystal structure guided elaboration [ 82 ]. In this instance, a cysteine was introduced at position 166 in the ATP binding site of PDK1 kinase and then coupled to a diaminopyrimidine thiol to covalently bind to the protein.…”

Section: Vbsmentioning

confidence: 99%

Fragment-Based Design of Kinase Inhibitors: A Practical Guide

Erickson

2015

Methods in Molecular Biology

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Fragment-based drug design has become an important strategy for drug design and development over the last decade. It has been used with particular success in the development of kinase inhibitors, which are one of the most widely explored classes of drug targets today. The application of fragment-based methods to discovering and optimizing kinase inhibitors can be a complicated and daunting task; however, a general process has emerged that has been highly fruitful. Here a practical outline of the fragment process used in kinase inhibitor design and development is laid out with specific examples. A guide to the overall process from initial discovery through fragment screening, including the difficulties in detection, to the computational methods available for use in optimization of the discovered fragments is reported.

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Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery

Cited by 77 publications

References 17 publications

Fragment Based Drug Design: From Experimental to Computational Approaches

Fragment Based Drug Design: From Experimental to Computational Approaches

Exploration of Type II Binding Mode: A Privileged Approach for Kinase Inhibitor Focused Drug Discovery?

Fragment-Based Design of Kinase Inhibitors: A Practical Guide

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