Shifting the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one inhibitors towards the salt-inducible kinase (SIK) subfamily

Rak, Marcel; Tesch, Roberta; Berger, Lena M.; Shevchenko, Ekaterina; Raab, Monika; Tjaden, Amelie; Zhubi, Rezart; Balourdas, Dimitrios-Ilias; Joerger, A.C.; Poso, Antti; Krämer, Andreas; Elson, Lewis; Lučić, Aleksandar; Kronenberger, Thales; Hanke, Thomas; Strebhardt, Klaus; Sanhaji, Mourad; Knapp, S.

doi:10.1016/j.ejmech.2023.115347

Cited by 8 publications

(22 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To elucidate the binding mode of the new series of 3-aminopyrazole-based macrocycles, JA310 ( 21c ) was co-crystallized with MST3, and the structure of the complex was determined at 1.64 Å resolution. Intriguingly, superimposition of this structure onto the structure of the MST3 AMP-PNP complex (PDB: 4QML), 34 the apo structure (PDB: 3CKW), or previously published MST3-inhibitor complexes 34–36 revealed a large-scale induced-fit movement upon macrocycle binding. This movement was characterized by a rotation and tilting of the upper lobe toward the C-lobe ( Figure 4A ), with large shifts of some of the β-strand backbone atoms by up to 8 Å and reorientation of the αC helix (including disruption of the K65-E82 salt bridge).…”

Section: Resultsmentioning

confidence: 88%

See 1 more Smart Citation

Synthesis of pyrazole-based macrocycles leads to a highly selective inhibitor for MST3

Amrhein,

Berger,

Balourdas

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

MST1, MST2, MST3, MST4, and YSK1 are conserved members of the mammalian sterile 20 kinase (MST) family. MSTs regulate key cellular functions such as cell proliferation, cell migration, metabolic regulation, and cell polarity. The MST3 isozyme plays a role in regulation of cell growth, autophagy and apoptosis, and its dysregulation has been linked to the occurrence of high-grade tumors with poor survival prognosis. To date, there are no isoform-selective inhibitors available that could be used for validating the role of MST3 in tumorigenesis and to assess its potential as an anti-cancer target for drug development. To this end, we have designed a new series of 3-aminopyrazole-based macrocycles based on the structure of an acyclic promiscuous kinase inhibitor. By varying moieties targeting the solvent-exposed region and optimizing the linker, macrocycle JA310 (21c) was synthesized. JA310 exhibited high cellular potency for MST3 with an EC50 = 106 nM and excellent kinome-wide selectivity with significantly lower cellular activity on the closely related kinase MST4 (EC50 = 1.4 uM). The high-resolution crystal structure of the MST3-JA310 complex provided intriguing insights into the distinct binding mode of the macrocycle, which was associated with large-scale structural rearrangements, including concerted induced-fit movements of the glycine-rich loop, the alphaC helix, and the activation loop. In summary, the developed macrocyclic MST3 inhibitor, JA310, demonstrates the utility of macrocyclization for the design of highly selective inhibitors and presents a first chemical probe for MST3.

show abstract

Section: Resultsmentioning

confidence: 88%

“…There was clear electron density for the whole activation loop, whereas this region was largely unresolved (indicating high conformational flexibility) in previously published inhibitor structures of unphosphorylated MST3 kinase domain. 35,36 An animation of the structural rearrangements has been uploaded as a supporting video.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of pyrazole-based macrocycles leads to a highly selective inhibitor for MST3

Amrhein,

Berger,

Balourdas

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…There was clear electron density for the whole activation loop, whereas this region was largely unresolved (indicating high conforma- tional flexibility) in previously published inhibitor structures of unphosphorylated MST3 kinase domain. 34,35 An animation of the structural rearrangements has been uploaded as a Supporting Video.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…To elucidate the binding mode of the new series of 3-aminopyrazole-based macrocycles, JA310 ( 21c ) was cocrystallized with MST3, and the structure of the complex was determined at 1.64 Å resolution. Intriguingly, superimposition of this structure onto the structure of the MST3 AMP–PNP complex (PDB: 4QML), the apo structure (PDB: 3CKW), or previously published MST3-inhibitor complexes ,, revealed a large-scale induced-fit movement upon macrocycle binding. This movement was characterized by a rotation and tilting of the upper lobe toward the C-lobe (Figure A), with large shifts of some of the β-strand backbone atoms by up to 8 Å and reorientation of the αC helix (including disruption of the K65-E82 salt bridge).…”

Section: Resultsmentioning

confidence: 99%

“…The typically formed small β-sheet, which is seen in the ATP analogue complex around G177, was disrupted in the complex with the macrocycle, and an additional short α-helical segment formed extending from residues 183–188. There was clear electron density for the whole activation loop, whereas this region was largely unresolved (indicating high conformational flexibility) in previously published inhibitor structures of unphosphorylated MST3 kinase domain. , An animation of the structural rearrangements has been uploaded as a Supporting Video.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis of Pyrazole-Based Macrocycles Leads to a Highly Selective Inhibitor for MST3

Amrhein,

Berger,

Balourdas

et al. 2023

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

MST1, MST2, MST3, MST4, and YSK1 are conserved members of the mammalian sterile 20-like serine/ threonine (MST) family that regulate cellular functions such as proliferation and migration. The MST3 isozyme plays a role in regulating cell growth and apoptosis, and its dysregulation has been linked to high-grade tumors. To date, there are no isoform-selective inhibitors that could be used for validating the role of MST3 in tumorigenesis. We designed a series of 3-aminopyrazole-based macrocycles based on the structure of a promiscuous inhibitor. By varying the moieties targeting the solvent-exposed region and optimizing the linker, macrocycle JA310 (21c) was synthesized. JA310 exhibited high cellular potency for MST3 (EC 50 = 106 nM) and excellent kinome-wide selectivity. The crystal structure of the MST3−JA310 complex provided intriguing insights into the binding mode, which is associated with large-scale structural rearrangements. In summary, JA310 demonstrates the utility of macrocyclization for the design of highly selective inhibitors and presents the first chemical probe for MST3.

show abstract

The structures of salt-inducible kinase 3 in complex with inhibitors reveal determinants for binding and selectivity

Öster,

Castaldo,

de Vries

et al. 2024

Journal of Biological Chemistry

View full text Add to dashboard Cite

Shifting the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one inhibitors towards the salt-inducible kinase (SIK) subfamily

Cited by 8 publications

References 60 publications

Synthesis of pyrazole-based macrocycles leads to a highly selective inhibitor for MST3

Synthesis of pyrazole-based macrocycles leads to a highly selective inhibitor for MST3

Synthesis of Pyrazole-Based Macrocycles Leads to a Highly Selective Inhibitor for MST3

The structures of salt-inducible kinase 3 in complex with inhibitors reveal determinants for binding and selectivity

Contact Info

Product

Resources

About