Verification of a Designed Intramolecular Hydrogen Bond in a Drug Scaffold by Nuclear Magnetic Resonance Spectroscopy

Jansma, Ariane; Zhang, Qiong; Li, Bing; Ding, Qiang; Uno, Tetsuo; Bursulaya, Badry; Liu, Yi; Furet, Pascal; Gray, Nathanael S.; Geierstanger, Bernhard H.

doi:10.1021/jm700983a

Cited by 38 publications

(40 citation statements)

References 39 publications

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“…Replacing the aliphatic amine of FIIN-1 with a 4-(4-methylpiperazin-1-yl) aniline group, which is a stronger hinge binder, compensates for the loss of potency, and FIIN-2 potently inhibits WT FGFRs (EC 50 s in the 1-to 93-nM range) and the gatekeeper mutant of FGFR2 (EC 50 of 58 nM). FIIN-3 incorporates a pyrimidyl urea core that forms an intramolecular H-bond, thereby forming a pseudo six-membered ring, a design feature of BGJ398 (39,52). The H-bond of this pseudo ring was envisioned to provide greater rotatory flexibility to the dichlorodimethoxylphenyl group of FIIN-3, which could better tolerate the methionine gatekeeper.…”

Section: Significancementioning

confidence: 99%

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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169

132

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The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.drug discovery | cancer drug resistance | kinase inhibitor | structure-based drug design R eceptor tyrosine kinases (RTKs) serve as critical sensors of extracellular cues that activate a myriad of intracellular signaling pathways to regulate cell state. There are 58 receptor tyrosine kinases in the human genome, and many have been demonstrated to be constitutively activated through amplification or mutation in particular cancers. The signals emanating from these RTKs, such as epidermal growth factor receptor (EGFR), FGF receptor (FGFR), platelet-derived growth factor receptor (PDGFR), protein kinase Kit (KIT), and protein kinase c-Met (MET), have been pharmacologically proven to be essential to the survival of cancers expressing mutant forms of these proteins. However, rapid resistance to monotherapy with first-generation RTK inhibitors has been universally observed. Resistance typically arises from the emergence of cancer cells expressing mutant forms of RTKs that are impervious to the action of first-generation drugs or from the activation of by-pass signaling mechanisms. Resistance can be overcome by developing new inhibitors that target the mutant RTK directly or target bypass signaling mechanisms. Indeed this approach has been deployed succes...

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Section: Significancementioning

confidence: 99%

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

169

132

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“…Increasing steric hindrance from hydroxylamine to O - tert- butylhydroxylamine actually resulted in a small preference for the formation of the Z -diastereomer. 14 In contrast, O -TMS-hydroxylamine gave increased diastereoselectivity for the desired E -oxime isomer. To explain the observed stereoselectivity, we proposed that the electron-withdrawing nature of the silicon substituent in O -TMS-hydroxylamine 15 slowed the stereodefining elimination step of oxime formation (Scheme 2).…”

mentioning

confidence: 99%

N–N Bond-Forming Cyclization for the One-Pot Synthesis of N-Aryl[3,4-d]pyrazolopyrimidines

2012

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An efficient one-pot synthesis of N-aryl[3,4-d]pyrazolopyrimidines in good yield and under mild reaction conditions is described. By exploiting electron-deficient hydroxylamines, the substituted oxime products were formed with very high E-diastereoselectivity. The key step utilizes a cyclization reaction upon an oxime derived from hydroxylamine-O-sulfonic acid to form the N–N bond of the product.

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“…[72] with a secondary amine, and compound 16 [73] with an ester linkage which were used to study how substitution patterns affected passage of nNOS inhibitors across the BBB [105]. The addition of an intramolecular HB is another known strategy used in PK and BBB optimisation of novel inhibitors for a variety of enzymes [107][108][109][110][111]. In an effort to exploit this strategy, nNOS aminopyridine inhibitors were designed with intramolecular hydrogen bonding motifs in the hope of improving cell membrane permeability [112].…”

Section: Pharmacokinetics Of Nnos Inhibitorsmentioning

confidence: 99%

Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations

Curtin¹,

Kinsella²,

Stephens

2015

CMC

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Neuronal nitric oxide synthase (nNOS) produces the key signalling mediator nitric oxide, (NO). This gaseous, free radical molecule modulates a vast array of biological processes, from vascular pressure to immune responses and neurological signalling cascades. Overproduction of NO has been implicated in conditions including Alzheimer's disease, Parkinson's disease and schizophrenia. Inhibition of nNOS therefore offers a potential therapeutic approach for treatment of these conditions. This endeavour is made more complex by the fact that there are two other isoforms of nitric oxide synthase (NOS), endothelial NOS (eNOS) and inducible NOS (iNOS). The selectivity of nNOS inhibitors is therefore a key concern for therapeutic development. This review explores recent advances in the field of selective nNOS inhibition. A particular focus is placed on computational approaches towards the rational design of selective nNOS ligands with improved pharmacokinetic properties. These ligands have been targeted at four key binding sites of the nNOS enzyme -the tetrahydrobiopterin, calmodulin, nicotinamide adenine dinucleotide phosphate (NADPH) and arginine binding sites. The binding sites, and the compounds used to inhibit them, will be discussed in turn, along with the computational methods which have been employed in the field of nNOS inhibition.

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Verification of a Designed Intramolecular Hydrogen Bond in a Drug Scaffold by Nuclear Magnetic Resonance Spectroscopy

Cited by 38 publications

References 39 publications

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

N–N Bond-Forming Cyclization for the One-Pot Synthesis of N-Aryl[3,4-d]pyrazolopyrimidines

Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations

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