Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors

Liang, Jun; Abbema, Anne van; Balázs, Mercedesz; Barrett, Kathy; Berezhkovsky, Leo; Blair, Wade; Chang, Christine; Delarosa, Donnie; DeVoss, Jason; Driscoll, James P.; Eigenbrot, Charles; Ghilardi, Nico; Gibbons, Paul; Halladay, Jason; Johnson, Adam R.; Kohli, Pawan Bir; Lai, Yingjie; Liu, Yanzhou; Lyssikatos, Joseph P.; Mantik, Priscilla; Menghrajani, Kapil; Murray, J.M.; Peng, Ivan; Sambrone, Amy; Shia, S.; Shin, Young Geun; Smith, Jan; Sohn, Sue J.; Tsui, Vickie; Ultsch, Mark; Wu, Lawren C.; Xiao, Yisong; Yang, Wenqian; Young, Judy; Zhang, Birong; Zhu, Bing‐Yan; Magnuson, Steven

doi:10.1021/jm400266t

Cited by 79 publications

(78 citation statements)

References 100 publications

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“…Despite high expression levels and good solution behavior, this fragment of TYK2 failed to crystallize in its apo-state. Addition of a TYK2-specific ATP-competitive inhibitor (24) to the protein sample enabled crystallization, and we obtained a structure of the pseudokinase-kinase module at a resolution of 2.8 Å (Table S1 and Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

Structure of the pseudokinase–kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

Lupardus¹,

Ultsch²,

Wallweber³

et al. 2014

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

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Janus kinases (JAKs) are receptor-associated multidomain tyrosine kinases that act downstream of many cytokines and interferons. JAK kinase activity is regulated by the adjacent pseudokinase domain via an unknown mechanism. Here, we report the 2.8-Å structure of the two-domain pseudokinase-kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudokinase and kinase interact near the kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and "exon 12" JAK2 mutations, results in increased kinase activity in vitro. These data indicate that JAK pseudokinases are autoinhibitory domains that hold the kinase domain inactive until receptor dimerization stimulates transition to an active state. JAK1 | JAK3H elical bundle cytokines of the interleukin and IFN families regulate a wide variety of immune and cellular growth responses (1). These signaling pathways are initiated by cytokinemediated receptor dimerization and subsequent activation of nonreceptor tyrosine kinases called Janus kinases (JAKs) that are associated with the receptor intracellular domains (2). JAK activation leads to phosphorylation of the receptor and recruitment of STAT family transcription factors, which are then phosphorylated by the JAK and translocated to the nucleus where they induce gene transcription. The JAK family consists of four members (JAK1, JAK2, JAK3, and tyrosine kinase 2 or TYK2), each of which binds a distinct set of cytokine receptor subtypes and hence has a unique gene knockout phenotype, ranging from embryonic lethality due to neuronal and erythropoietic defects (JAK1 and JAK2, respectively) (3-5), to profound immune system deficiencies (JAK3 and TYK2) (6).The JAK kinases are large (∼1,150-aa) multidomain proteins whose primary sequences were initially organized into seven JAK-homology (JH) domains that reflected distinct regions of high sequence homology (7). Subsequent structure predictions indicated that JAKs contain four distinct domains: N-terminal 4.1, Ezrin, Radixin, Moesin (FERM) and Src homology 2 (SH2) domains, followed by C-terminal pseudokinase and kinase domains (7,8) (Fig. 1A). The FERM and SH2 domains constitute the receptor-binding module (2), whereas the pseudokinase, which has a canonical kinase fold but lacks key catalytic residues, is thought to regulate kinase activity. Deletion of the pseudokinase in JAK2 and JAK3 increases basal kinase activity and deregulates signaling through cognate receptors (9, 10). Additionally, the JAK2 pseudokinase and kinase domains have been reported to coimmunoprecipitate, and coexpression of the JAK2 pseudokinase domain inhibits activity of the isolated kinase domain (10). Recent work on the JAK2 pseudokinase domain indicates that it has weak catalytic activity and autophosphorylates two inhibitory sites within the SH2-pseudokinase linker and pseudokinase...

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Section: Resultsmentioning

confidence: 99%

Structure of the pseudokinase–kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

Lupardus¹,

Ultsch²,

Wallweber³

et al. 2014

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

Self Cite

186

241

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“…This study suggested that selectivity could be achieved not only by directly targeting sequence differences but also by utilizing the overall discrepancy in P-loop conformation or flexibility. 58 X-ray structures of a C-2 methyl analogue 55 complexed with JAK1 (PDB code: 4EHZ) and JAK2 (PDB code: 4F09) revealed differential protein−ligand interactions between these two isozymes, providing an opportunity for improving selectivity (Figure 23). Structure-based design culminated in the identification of a C-2 hydroxyethyl imidazopyrrolopyridine derivative 56 as a potent JAK1 inhibitor with high selectivity over JAK2.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Strategies for the Discovery of Target-Specific or Isoform-Selective Modulators

et al. 2015

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Currently, the creation of class- and isoform-selective modulators of biologically important targets is a particularly challenging problem because different isoforms within a protein family often show striking similarity in spatial quaternary structure, especially at the catalytic sites or binding pockets. Therefore, an understanding of both the precise three-dimensional structure of the target protein and the mechanisms of action of modulators is important for developing more effective and selective agents. In this Perspective, we discuss currently available rational design strategies for obtaining class- and isoform-selective inhibitors and we illustrate these strategies with the aid of specific examples from the recent literature. The strategies covered include: (1) target-derived (-dependent) de novo drug discovery methodologies, and (2) follow-on derivatization approaches from initially identified active molecules (hit-to-lead and lead-to-candidate efforts). We also comment on prospects for further development and integration of strategies to achieve target-specific or isoform-selective inhibition.

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“…Based on lead molecule 60, the authors further explored the SAR, focusing on modifications of the phenyl group and the cyclopropylamide moiety [119]. Compounds 61 and 62 showed improved TYK2 enzyme and cell potency, as well as cellular JAK1 and JAK2 selectivity well above that of 60.…”

Section: Tyk2-selective Inhibitorsmentioning

confidence: 99%

Selective JAK Inhibitors

et al. 2014

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Consisting of four members, JAK1, JAK2, JAK3 and TYK2, the JAK kinases have emerged as important targets for proliferative and immune-inflammatory disorders. Recent progress in the discovery of selective inhibitors has been significant, with selective compounds now reported for each isoform. This article summarizes the current state-of-the-art with a discussion of the most recently described selective compounds. X-ray co-crystal structures reveal the molecular reasons for the observed biochemical selectivity. A concluding analysis of JAK inhibitors in the clinic highlights increased clinical trial activity and diversity of indications. Selective JAK inhibitors, as single agents or in combination regimens, have a very promising future in the treatment of oncology, immune and inflammatory diseases.

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Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors

Cited by 79 publications

References 100 publications

Structure of the pseudokinase–kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

Structure of the pseudokinase–kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

Strategies for the Discovery of Target-Specific or Isoform-Selective Modulators

Selective JAK Inhibitors

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