Chemical and Computational Methods for the Characterization of Covalent Reactive Groups for the Prospective Design of Irreversible Inhibitors

Flanagan, Mark E.; Abramite, J. A.; Anderson, D. Keith; Aulabaugh, Ann; Dahal, Upendra P.; Gilbert, Adam M.; Li, Chao; Montgomery, Justin I.; Oppenheimer, Stacey R.; Ryder, Tim F.; Schuff, Brandon P.; Uccello, Daniel P.; Walker, Gregory S.; Wu, Yan; Brown, Matthew F.; Chen, Jinshan M.; Hayward, Matthew M.; Noe, Mark C.; Obach, R. Scott; Philippe, Laurence; Shanmugasundaram, Veerabahu; Shapiro, Michael J.; Starr, Jeremy T.; Stroh, Justin G.; Che, Ye

doi:10.1021/jm501412a

Cited by 252 publications

(367 citation statements)

References 39 publications

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“…We and others have also developed mutant-selective inhibitors of the drug-resistant EGFR T790M that react covalently with Cys797. WZ4002 21 ( 8 ) is a pyrimidine-based inhibitor with an acrylamide “warhead” 22 that potently inhibits EGFR T790M. Recently three other groups have also reported the development of covalent JAK3 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Development of Selective Covalent Janus Kinase 3 Inhibitors

Akahane

McNally

et al. 2015

J. Med. Chem.

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The Janus Kinases (JAKs) and their downstream effectors Signal Transducer and Activator of Transcription proteins (STATs) form a critical immune cell signaling circuit, which is of fundamental importance in innate immunity, inflammation and hematopoiesis and dysregulation is frequently observed in immune disease and cancer. The high degree of structural conservation of the JAK ATP binding pockets has posed a considerable challenge to medicinal chemists seeking to develop highly selective inhibitors as pharmacological probes and as clinical drugs. Here we report the discovery and optimization of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of structure-activity-relationship (SAR) utilizing biochemical and transformed Ba/F3 cellular assays resulted in identification of potent and selective inhibitors such as compounds 9 and 45. A 2.9 Å co-crystal structure of JAK3 in complex with 9 confirms the covalent interaction. Compound 9 exhibited decent pharmacokinetic properties and is suitable for use in vivo. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology.

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Section: Introductionmentioning

confidence: 99%

Development of Selective Covalent Janus Kinase 3 Inhibitors

Akahane

McNally

et al. 2015

J. Med. Chem.

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“…37 The acrylamide analogue of SML-8-73-1 (2) exhibits a higher rate constant k inact than α-chloroacetamide-containing SML-8-73-1, although it is generally believed that the α-chloroacetamide warhead is more reactive toward cysteine group than acrylamide. 38 We postulated that longer length between the β-phosphate and the reactive site of the acrylamide in 2 may be optimal for the requisite covalent bond formation. Analogues with a propyl linker (13, 14) improved the affinity to KRAS G12C, possibly due to a combinatory effect of optimal spacing, and better trajectory of the electrophile warhead toward nucleophilic substitution of Cys12.…”

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confidence: 99%

Covalent Guanosine Mimetic Inhibitors of G12C KRAS

Xiong

Hunter³

et al. 2016

ACS Med. Chem. Lett.

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Ras proteins are members of a large family of GTPase enzymes that are commonly mutated in cancer where they act as dominant oncogenes. We previously developed an irreversible guanosine-derived inhibitor, SML-8-73-1, of mutant G12C RAS that forms a covalent bond with cysteine 12. Here we report exploration of the structure−activity relationships (SAR) of hydrolytically stable analogues of SML-8-73-1 as covalent G12C KRAS inhibitors. We report the discovery of difluoromethylene bisphosphonate analogues such as compound 11, which, despite exhibiting reduced efficiency as covalent G12C KRAS inhibitors, remove the liability of the hydrolytic instability of the diphosphate moiety present in SML-8-73-1 and provide the foundation for development of prodrugs to facilitate cellular uptake. The SAR and crystallographic results reaffirm the exquisite molecular recognition that exists in the diphosphate region of RAS for guanosine nucleotides which must be considered in the design of nucleotide-competitive inhibitors.

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“…Unsubstituted acrylamides are found in clinically approved agents and are considered mild electrophiles that react with nucleophilic cysteines when receptor and ligand geometry is optimized. 28 …”

Section: Resultsmentioning

confidence: 99%

Novel K-Ras G12C Switch-II Covalent Binders Destabilize Ras and Accelerate Nucleotide Exchange

Nnadi

Jenkins

Gentile

et al. 2018

J. Chem. Inf. Model.

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The success of targeted covalent inhibitors in the global pharmaceutical industry has led to a resurgence of covalent drug discovery. However, covalent inhibitor design for flexible binding sites remains a difficult task due to lack of methodological development. Here, we compared covalent docking to empirical electrophile screening against the highly dynamic target K-RasG12C. While the overall hit rate of both methods was comparable, we were able to rapidly progress a docking hit to a potent irreversible covalent inhibitor that modifies the inactive, GDP-bound state of K-RasG12C. Hydrogen-deuterium exchange mass spectrometry was used to probe the protein dynamics of compound binding to the switch-II pocket and subsequent destabilization of the nucleotide-binding region. SOS-mediated nucleotide exchange assays showed that, contrary to prior switch-II pocket inhibitors, these compounds appear to accelerate nucleotide exchange. This study highlights the efficiency of covalent docking as a tool for the discovery of chemically novel hits against challenging targets.

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Chemical and Computational Methods for the Characterization of Covalent Reactive Groups for the Prospective Design of Irreversible Inhibitors

Cited by 252 publications

References 39 publications

Development of Selective Covalent Janus Kinase 3 Inhibitors

Development of Selective Covalent Janus Kinase 3 Inhibitors

Covalent Guanosine Mimetic Inhibitors of G12C KRAS

Novel K-Ras G12C Switch-II Covalent Binders Destabilize Ras and Accelerate Nucleotide Exchange

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