Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors

Kulagowski, Janusz J.; Blair, Wade; Bull, Richard J.; Chang, Christine; Deshmukh, Gauri; Dyke, Hazel J.; Eigenbrot, Charles; Ghilardi, Nico; Gibbons, Paul; Harrison, T.; Hewitt, Peter R.; Liimatta, Marya; Hurley, Christopher A.; Johnson, Adam R.; Johnson, Tony; Kenny, Jane R.; Kohli, Pawan Bir; Maxey, Robert; Mendonca, Rohan; Mortara, Kyle; Murray, J.M.; Narukulla, Raman; Shia, S.; Steffek, Micah; Ubhayakar, Savita; Ultsch, Mark; Abbema, Anne van; Ward, Stuart I.; Waszkowycz, Bohdan; Zak, Mark

doi:10.1021/jm300438j

Cited by 87 publications

(69 citation statements)

References 45 publications

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“…15,16) Among them, C2-methyl imidazopyrrolopyridine (1, Fig. 1) shows potent and selective inhibitory activity against JAK1, i.e., K i of 10 nM, and JAK1 selectivity of 20, 16) which guided us to design a novel JAK1-selective inhibitor based on a pyrrolopyridine scaffold.…”

Section: )mentioning

confidence: 99%

“…14) Despite a high level of interest in selective JAK inhibitors and their potential for immune-modulating therapies, only a few JAK1 inhibitors have been reported to date. 15,16) Among them, C2-methyl imidazopyrrolopyridine (1, Fig. 1) shows potent and selective inhibitory activity against JAK1, i.e., K i of 10 nM, and JAK1 selectivity of 20,16) which guided us to design a novel JAK1-selective inhibitor based on a pyrrolopyridine scaffold.…”

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confidence: 99%

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4-Amino-pyrrolopyridine-5-carboxamide: A Novel Scaffold for JAK1-Selective Inhibitors

Shin

Kim

Chong

2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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Despite a high level of interest in selective Janus kinase 1 (JAK1) inhibitors and their potential for the treatment of inflammatory diseases such as rheumatoid arthritis (RA), only a few such inhibitors have been reported to date. In this study, a novel 4-amino-1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold was designed through structural modification of the potent JAK1-selective inhibitor, C2-methyl imidazopyrrolopyridine. Among the series studied, the 4-(2-aminoethyl)amino-pyrrolopyridine derivative, 2j, exhibited a significant 24.7-fold JAK1/JAK2 selectivity along with reasonable inhibitory activity against JAK1 (IC 50 2.2 µM). The noticeable JAK1-selectivity of 2j was then tackled through a molecular docking study, which showed that the aminoethyl functionality of 2j is well positioned to discriminate the subtle but significant difference in the size of the ligand binding sites between JAK1 and JAK2.Key words Janus kinase 1 (JAK1); pyrrolopyridine; rheumatoid arthritisThe Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, a major signaling cascade in response to inflammatory and proliferative signals, consists of the Janus protein tyrosine kinase family (JAK3, JAK2, JAK1, and TYK2) and STAT family of transcription factors. Upon ligand-receptor binding, the JAKs get activated, resulting in the phosphorylation, dimerization, and nuclear translocation of the downstream STAT proteins, which regulate the transcription of STAT-dependent genes. Depending on the specific cytokines coupled with JAKs, ligand-receptor binding culminates in an intracellular response such as an immune function, 1) inflammation, 2) or hematopoiesis. 3,4) For instance, the gamma common (γ c ) family of cytokines, i.e., interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21, is exclusively associated with JAK1 and JAK3, 5) and a loss-of-function mutation in the γ c chain or JAK3 results in severe combined immunodeficiency (SCID). As a result, abrogation of signaling by γ c -cytokines through the inhibition of γ c -linked JAK3 has long been regarded as an attractive target for the treatment of immunologic disorders such as rheumatoid arthritis (RA). 2,6) Pfizer's Xeljanz (Tofacitinib, CP-690550), the first-in-class JAK inhibitor approved for the treatment of RA, 7) was initially reported to be a selective JAK3 inhibitor, 6) spurring many pharmaceutical companies to launch JAK3 medicinal chemistry programs.However, it has become clear that tofacitinib is not as specific for JAK3 as initially thought, but it is rather a potent pan-JAK inhibitor, 8) suggesting that the clinical efficacy of the compound against RA is unlikely to be driven by the selective inhibition of JAK3. In addition, accumulated evidence has revealed that in signal transduction through γ c -containing cytokine receptors, JAK1 plays a dominant role, while JAK3 exhibits only a secondary functional activity that merely enhances the effect of JAK1.9-13) Accordingly, JAK1 inhibition has become a relevant treatment option for RA. For successful ...

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confidence: 99%

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confidence: 99%

4-Amino-pyrrolopyridine-5-carboxamide: A Novel Scaffold for JAK1-Selective Inhibitors

Shin

Kim

Chong

2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The compound 3e with the most significant JAK1/ JAK2 selectivity was therefore docked into the ATP-binding site of JAK1 (PDB ID = 4E5W) 11 and JAK2 (PDB ID = 2B7A) 20 by using the flexible ligand docking software Glide incorporated into the Schrödinger molecular modeling software suite (Fig. 2).…”

Section: Notesmentioning

confidence: 99%

“…Thus, in order to serve as an ideal therapeutic agent to target RA, a JAK1 inhibitor needs to achieve selective inhibition of JAK1 over other JAK isozymes. 10 Recently, several chemical entities have been identified with potent JAK1 inhibitory activities, [11][12] but with relatively low (6.4-20 fold) selectivity over JAK2.…”

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De Novo Design of 2-Amino-4-Alkylaminoquinazoline-7-Carboxamides as Potential Scaffold for JAK1-Selective Inhibitors

Kim¹,

Kim²,

Chong

2014

Bulletin of the Korean Chemical Society

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“…Thus, this water molecule is in a binding site that provides the maximum number of hydrogen-bonding partners, suggesting that the enthalpic gain resulting from the formation of hydrogen bonds likely compensates the entropic penalty incurred by restriction of rotational and translational degrees of freedom through sequestration from bulk water. 9 Interestingly, a water molecule in a closely equivalent location occurs in six further FGFR1−ligand complexes (PDB codes: 2FGI, 10 3TTO, 11 3C4F, 12 3GQL, 13 3RHX, 14 and 1AGW) 15 and also in ligand-bound complexes of other kinases such as ABL (PDB code: 2GQG, 16 1OPJ), 17 SRC (PDB code: 1Y57), 18 or JAK1 (PDB code: 4E5W; 19 Supporting Information Figure S1). In some of the structures, the conserved water molecule mediates a hydrogen bond to the ligand, as observed for the FGFR1−1 complex; furthermore, it interconnects different structural features of the kinase domain (P-loop, Aloop, αC helix, β3 sheet) through hydrogen bonds.…”

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confidence: 99%

FGFR1 Kinase Inhibitors: Close Regioisomers Adopt Divergent Binding Modes and Display Distinct Biophysical Signatures

Klein

Tucker

Holdgate

et al. 2013

ACS Med. Chem. Lett.

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The binding of a ligand to its target protein is often accompanied by conformational changes of both the protein and the ligand. This is of particular interest, since structural rearrangements of the macromolecular target and the ligand influence the free energy change upon complex formation. In this study, we use X-ray crystallography, isothermal titration calorimetry, and surface-plasmon resonance biosensor analysis to investigate the binding of pyrazolylaminopyrimidine inhibitors to FGFR1 tyrosine kinase, an important anticancer target. Our results highlight that structurally close analogs of this inhibitor series interact with FGFR1 with different binding modes, which are a consequence of conformational changes in both the protein and the ligand as well as the bound water network. Together with the collected kinetic and thermodynamic data, we use the protein−ligand crystal structure information to rationalize the observed inhibitory potencies on a molecular level. KEYWORDS: Receptor tyrosine kinase, induced fit, protein−ligand interactions, X-ray crystallography, isothermal titration calorimetry, surface plasmon resonance M embers of the fibroblast growth factor receptor (FGFR) family (FGFR1 to 4) serve as high affinity receptors for the fibroblast growth factors (FGFs) 1 and are key mediators of both developmental and disease-associated angiogenesis. 2 They are heavily implicated in the pathogenesis of tumor vascularization in a number of different tumor types, including breast, 3 pancreatic, 4 prostate, 5 and ovarian 6 carcinomas. Hence, they have been seen as attractive targets for the development of therapeutic agents 7 aimed at inhibiting tumor growth and metastasis through blockade of neovascularization. Recently, Norman et al. reported on the discovery of pyrazolylaminopyrimidines as potent FGFR1 inhibitors and their structure-based optimization that led to the identification of compound 1 (Figure 1). 8 In our continuing studies aimed at optimizing ligand-binding site interactions, the substitution pattern of the 3,5-dimethoxyphenyl group of 1 was varied. Interestingly, a tight structure−activity relationship was observed: moving one methoxy function from the 5-to the 4-position (compound 2) resulted in a drop of inhibitory potency/binding affinity of almost 2 orders of magnitude (Figure 1). Intrigued by this finding, we set about investigating the interaction between FGFR1 kinase and the selected pyrazolylaminopyrimidine inhibitors 1−3 using structural and biophysical analysis. Comparisons of the inhibitor binding modes as well as the accompanying kinetic and thermodynamic signatures provide detailed insights into the molecular determinants governing the different affinities of these structurally close inhibitors toward FGFR1 kinase.The crystal structure of FGFR1 in complex with 1 revealed the inhibitor to bind as expected with the pyrazolylaminopyr-

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Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors

Cited by 87 publications

References 45 publications

4-Amino-pyrrolopyridine-5-carboxamide: A Novel Scaffold for JAK1-Selective Inhibitors

4-Amino-pyrrolopyridine-5-carboxamide: A Novel Scaffold for JAK1-Selective Inhibitors

De Novo Design of 2-Amino-4-Alkylaminoquinazoline-7-Carboxamides as Potential Scaffold for JAK1-Selective Inhibitors

FGFR1 Kinase Inhibitors: Close Regioisomers Adopt Divergent Binding Modes and Display Distinct Biophysical Signatures

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