7,8-Dichloro-1-oxo-β-carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes

Huber, Kilian; Brault, Laurent; Fedorov, O.; Gasser, Christelle; Filippakopoulos, P.; Bullock, Alex N.; Fabbro, Doriano; Trappe, Jörg; Schwaller, Jürg; Knapp, Stefan; Bracher, Franz

doi:10.1021/jm201286z

Cited by 67 publications

(67 citation statements)

References 51 publications

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“…[34] Against expectation, the compound proved to be completely inactive at the concentrations tested. Given that kinase inhibitors anchored to the hinge region through one or two halogen bonds have been described, [35] we probed if introducing a bromine atom to the 3- . QM relaxed torsional scan (3608 in 108 steps) of the tofacitinib side chain relative to the planar heterocyclic core.…”

Section: Resultsmentioning

confidence: 99%

Novel Hinge‐Binding Motifs for Janus Kinase 3 Inhibitors: A Comprehensive Structure–Activity Relationship Study on Tofacitinib Bioisosteres

et al. 2014

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The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7H-pyrrolo[2,3-d]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure-activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in silico models.

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Section: Resultsmentioning

confidence: 99%

Novel Hinge‐Binding Motifs for Janus Kinase 3 Inhibitors: A Comprehensive Structure–Activity Relationship Study on Tofacitinib Bioisosteres

et al. 2014

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“…The presence of multiple halogen bonds stabilizing protein− ligand complexes has also been reported by Knapp, Bracker, and co-workers in the complex of a 6,7-dichloro-substituted indole ligand with the carbonyl oxygens of the hinge region of the CDC-like kinase 3 (CLK3), 313 and in the complex of dichloro-substituted carbolines with PIM1 kinase (PIM = proviral integration site in moloney murine leukemia virus). 314 Baumil and co-workers have demonstrated that multiple Cl··· O halogen bonds are responsible for the selectivity of DRB (5,6-dichlorobenzimidazone-1-β-D-ribofuranoside) toward cyclin-dependent kinase 9 (Cdk9) (Cdk9 inhibition contributes to the anticancer effect of many Cdk inhibitors, and as a consequence its selective inhibition is of great interest). 315 DRB binding induces a conformational change in Cdk9, and binds via two Cl···O XBs (Figure 77), with the binding supplemented by an orthogonal NH···X HB to the chlorine atom's negative belt of electron density (PDB entry 3MY1).…”

Section: Analysis Of the Protein Data Bank: Halogen Bonds To Amino Acidsmentioning

confidence: 99%

Halogen Bonding in Supramolecular Chemistry

et al. 2015

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CONTENTS 1. Introduction to Halogen Bonding 7119 1.1. Nature of the Halogen Bond 7119 1.2. Scope of the Review 7120 2. Computational and Theoretical Investigations of Halogen Bonding 7120 2.1.Quantum Mechanics Methods 7120 2.2. σ-Hole Model of Halogen Bonding 7120 2.3. Other Contributions to the Nature of Halogen Bonding 7122 2.4. Recent Examples of Computationally Investigated Halogen-Bonded Complexes 7123 2.4.1. XB to Neutral Species 7123 2.4.2. XB to Anions 7126 2.4.3. XB in Protein−Ligand Complexes 7127 2.4.4. Electron-Transfer Processes Affected by XB Interactions 7127 2.5. Classical Force Field Calculations 7127 2.6. Conclusions and Outlook 7129 3. Gas-Phase Studies of Halogen-Bonding Interactions 7130 4. Halogen Bonding in the Solid State 7131 4.1. Introduction to Crystal Engineering and Functional Materials 7131 4.2. Fundamentals 7132 4.3. Halogen-Bonding Hierarchy 7134 4.3.1. Ranking Halogen-Bond Donors 7134 4.3.2. HB/XB Complementarity/Competition 7136 4.3.3. Predicting XBs 7138 4.4. Control of Solid-State Supramolecular Architectures 7138 4.4.1. Polymorphism 7138 4.4.2. Stoichiometry 7139 4.4.3. Tautomeric Control 7140 4.4.4. XBs Involving Metals and Metal-Bound XBs 7140 4.4.5. XB with Anions in the Solid State 4.5. Solid-State Architectures 4.6.

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“…Superpositions of the 58 Pim-1-inhibitor complexes submitted to the PDB using secondary-structure matching in Coot (Emsley & Cowtan, 2004) revealed that only three other inhibitors, -carboline ligand I (PDB entry 3cxw; Huber et al, 2012), -carboline ligand II (PDB entry 3cy2; Huber et al, 2012) and one of the 3H-benzo[4,5]-thieno[3,2-d]pyrimidin-4-one inhibitors (PDB entry 3jxw; Tao et al, 2009), also raise the P-loop. However, the conformation in compound 1 has the closest proximity to the 3 strand.…”

Section: P-loop Conformationmentioning

confidence: 99%

Flexibility of the P-loop of Pim-1 kinase: observation of a novel conformation induced by interaction with an inhibitor

et al. 2012

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PDB References: Pim-1, complex with compound 1, 3umx; complex with compound 2, 4eny; complex with compound 3, 4enx.The serine/threonine kinase Pim-1 is emerging as a promising target for cancer therapeutics. Much attention has recently been focused on identifying potential Pim-1 inhibitor candidates for the treatment of haematopoietic malignancies. The outcome of a rational drug-design project has recently been reported [Nakano et al. (2012), J. Med. Chem. 55, 5151-5156]. The report described the process of optimization of the structure-activity relationship and detailed from a medicinal chemistry perspective the development of a low-potency and nonselective compound initially identified from in silico screening into a potent, selective and metabolically stable Pim-1 inhibitor. Here, the structures of the initial in silico hits are reported and the noteworthy features of the Pim-1 complex structures are described. A particular focus was placed on the rearrangement of the glycine-rich P-loop region that was observed for one of the initial compounds, (Z)-7-(azepan-1-ylmethyl)-2-[(1H-indol-3-yl)methylidene]-6-hydroxy-1-benzofuran-3(2H)-one (compound 1), and was also found in all further derivatives. This novel P-loop conformation, which appears to be stabilized by an additional interaction with the 3 strand located above the binding site, is not usually observed in Pim-1 structures.

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7,8-Dichloro-1-oxo-β-carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes

Cited by 67 publications

References 51 publications

Novel Hinge‐Binding Motifs for Janus Kinase 3 Inhibitors: A Comprehensive Structure–Activity Relationship Study on Tofacitinib Bioisosteres

Novel Hinge‐Binding Motifs for Janus Kinase 3 Inhibitors: A Comprehensive Structure–Activity Relationship Study on Tofacitinib Bioisosteres

Halogen Bonding in Supramolecular Chemistry

Flexibility of the P-loop of Pim-1 kinase: observation of a novel conformation induced by interaction with an inhibitor

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