Exploring the NCS-382 Scaffold for CaMKII alpha Modulation: Synthesis, Biochemical Pharmacology, and Biophysical Characterization of Ph-HTBA as a Novel High-Affinity Brain-Penetrant Stabilizer of the CaMKII alpha Hub Domain

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Exploring the NCS-382 Scaffold for CaMKII alpha Modulation : Synthesis, Biochemical Pharmacology, and Biophysical Characterization of Ph-HTBA as a Novel High-Affinity Brain-Penetrant Stabilizer of the CaMKII alpha Hub Domain. / Tian, Yongsong; Shehata, Mohamed A.; Gauger, Stine Juul; Veronesi, Carolina; Hamborg, Louise; Thiesen, Louise; Bruus-Jensen, Jesper; Royssen, Johanne Schlieper; Leurs, Ulrike; Larsen, Anne Sofie G.; Krall, Jacob; Solbak, Sara M. O.; Wellendorph, Petrine; Frolund, Bente.

In: Journal of Medicinal Chemistry, Vol. 65, No. 22, 2022, p. 15066–15084.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Tian, Y, Shehata, MA, Gauger, SJ, Veronesi, C, Hamborg, L, Thiesen, L, Bruus-Jensen, J, Royssen, JS, Leurs, U, Larsen, ASG, Krall, J, Solbak, SMO, Wellendorph, P & Frolund, B 2022, 'Exploring the NCS-382 Scaffold for CaMKII alpha Modulation: Synthesis, Biochemical Pharmacology, and Biophysical Characterization of Ph-HTBA as a Novel High-Affinity Brain-Penetrant Stabilizer of the CaMKII alpha Hub Domain', Journal of Medicinal Chemistry, vol. 65, no. 22, pp. 15066–15084. https://doi.org/10.1021/acs.jmedchem.2c00805

APA

Tian, Y., Shehata, M. A., Gauger, S. J., Veronesi, C., Hamborg, L., Thiesen, L., Bruus-Jensen, J., Royssen, J. S., Leurs, U., Larsen, A. S. G., Krall, J., Solbak, S. M. O., Wellendorph, P., & Frolund, B. (2022). Exploring the NCS-382 Scaffold for CaMKII alpha Modulation: Synthesis, Biochemical Pharmacology, and Biophysical Characterization of Ph-HTBA as a Novel High-Affinity Brain-Penetrant Stabilizer of the CaMKII alpha Hub Domain. Journal of Medicinal Chemistry, 65(22), 15066–15084. https://doi.org/10.1021/acs.jmedchem.2c00805

Vancouver

Tian Y, Shehata MA, Gauger SJ, Veronesi C, Hamborg L, Thiesen L et al. Exploring the NCS-382 Scaffold for CaMKII alpha Modulation: Synthesis, Biochemical Pharmacology, and Biophysical Characterization of Ph-HTBA as a Novel High-Affinity Brain-Penetrant Stabilizer of the CaMKII alpha Hub Domain. Journal of Medicinal Chemistry. 2022;65(22):15066–15084. https://doi.org/10.1021/acs.jmedchem.2c00805

Author

Tian, Yongsong ; Shehata, Mohamed A. ; Gauger, Stine Juul ; Veronesi, Carolina ; Hamborg, Louise ; Thiesen, Louise ; Bruus-Jensen, Jesper ; Royssen, Johanne Schlieper ; Leurs, Ulrike ; Larsen, Anne Sofie G. ; Krall, Jacob ; Solbak, Sara M. O. ; Wellendorph, Petrine ; Frolund, Bente. / Exploring the NCS-382 Scaffold for CaMKII alpha Modulation : Synthesis, Biochemical Pharmacology, and Biophysical Characterization of Ph-HTBA as a Novel High-Affinity Brain-Penetrant Stabilizer of the CaMKII alpha Hub Domain. In: Journal of Medicinal Chemistry. 2022 ; Vol. 65, No. 22. pp. 15066–15084.

Bibtex

@article{31e5545dd9f74b429f7460065b2a7e94,
title = "Exploring the NCS-382 Scaffold for CaMKII alpha Modulation: Synthesis, Biochemical Pharmacology, and Biophysical Characterization of Ph-HTBA as a Novel High-Affinity Brain-Penetrant Stabilizer of the CaMKII alpha Hub Domain",
abstract = "Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII alpha) is a brain-relevant kinase and an emerging drug target for ischemic stroke and neurodegenerative disorders. Despite reported CaMKII alpha inhibitors, their usefulness is limited by low subtype selectivity and brain permeability. (E)-2-(5-Hydroxy-5,7,8,9-tetrahydro-6H-benzo[7]annulen-6-ylidene)acetic acid (NCS-382) is structurally related to the proposed neuromodulator, gamma-hydroxybutyric acid, and is a brain-penetrating high nanomolar-affinity ligand selective for the CaMKII alpha hub domain. Herein, we report the first series of NCS-382 analogs displaying improved affinity and preserved brain permeability. Specifically, we present Ph-HTBA (1i) with enhanced mid-nanomolar affinity for the CaMKII alpha binding site and a marked hub thermal stabilization effect along with a distinct CaMKII alpha Trp403 flip upon binding. Moreover, Ph-HTBA has good cellular permeability and low microsomal clearance and shows brain permeability after systemic administration to mice, signified by a high Kp, uu value (0.85). Altogether, our study highlights Ph-HTBA as a promising candidate for CaMKII alpha-associated pharmacological interventions and future clinical development.",
keywords = "PROTEIN-KINASE-II, GAMMA-HYDROXYBUTYRIC ACID, GHB LIGANDS DESIGN, ACCURATE DOCKING, SODIUM OXYBATE, BINDING, MECHANISM, RECEPTOR, ANALOGS, GLIDE",
author = "Yongsong Tian and Shehata, {Mohamed A.} and Gauger, {Stine Juul} and Carolina Veronesi and Louise Hamborg and Louise Thiesen and Jesper Bruus-Jensen and Royssen, {Johanne Schlieper} and Ulrike Leurs and Larsen, {Anne Sofie G.} and Jacob Krall and Solbak, {Sara M. O.} and Petrine Wellendorph and Bente Frolund",
year = "2022",
doi = "10.1021/acs.jmedchem.2c00805",
language = "English",
volume = "65",
pages = "15066–15084",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "22",

}

RIS

TY - JOUR

T1 - Exploring the NCS-382 Scaffold for CaMKII alpha Modulation

T2 - Synthesis, Biochemical Pharmacology, and Biophysical Characterization of Ph-HTBA as a Novel High-Affinity Brain-Penetrant Stabilizer of the CaMKII alpha Hub Domain

AU - Tian, Yongsong

AU - Shehata, Mohamed A.

AU - Gauger, Stine Juul

AU - Veronesi, Carolina

AU - Hamborg, Louise

AU - Thiesen, Louise

AU - Bruus-Jensen, Jesper

AU - Royssen, Johanne Schlieper

AU - Leurs, Ulrike

AU - Larsen, Anne Sofie G.

AU - Krall, Jacob

AU - Solbak, Sara M. O.

AU - Wellendorph, Petrine

AU - Frolund, Bente

PY - 2022

Y1 - 2022

N2 - Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII alpha) is a brain-relevant kinase and an emerging drug target for ischemic stroke and neurodegenerative disorders. Despite reported CaMKII alpha inhibitors, their usefulness is limited by low subtype selectivity and brain permeability. (E)-2-(5-Hydroxy-5,7,8,9-tetrahydro-6H-benzo[7]annulen-6-ylidene)acetic acid (NCS-382) is structurally related to the proposed neuromodulator, gamma-hydroxybutyric acid, and is a brain-penetrating high nanomolar-affinity ligand selective for the CaMKII alpha hub domain. Herein, we report the first series of NCS-382 analogs displaying improved affinity and preserved brain permeability. Specifically, we present Ph-HTBA (1i) with enhanced mid-nanomolar affinity for the CaMKII alpha binding site and a marked hub thermal stabilization effect along with a distinct CaMKII alpha Trp403 flip upon binding. Moreover, Ph-HTBA has good cellular permeability and low microsomal clearance and shows brain permeability after systemic administration to mice, signified by a high Kp, uu value (0.85). Altogether, our study highlights Ph-HTBA as a promising candidate for CaMKII alpha-associated pharmacological interventions and future clinical development.

AB - Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII alpha) is a brain-relevant kinase and an emerging drug target for ischemic stroke and neurodegenerative disorders. Despite reported CaMKII alpha inhibitors, their usefulness is limited by low subtype selectivity and brain permeability. (E)-2-(5-Hydroxy-5,7,8,9-tetrahydro-6H-benzo[7]annulen-6-ylidene)acetic acid (NCS-382) is structurally related to the proposed neuromodulator, gamma-hydroxybutyric acid, and is a brain-penetrating high nanomolar-affinity ligand selective for the CaMKII alpha hub domain. Herein, we report the first series of NCS-382 analogs displaying improved affinity and preserved brain permeability. Specifically, we present Ph-HTBA (1i) with enhanced mid-nanomolar affinity for the CaMKII alpha binding site and a marked hub thermal stabilization effect along with a distinct CaMKII alpha Trp403 flip upon binding. Moreover, Ph-HTBA has good cellular permeability and low microsomal clearance and shows brain permeability after systemic administration to mice, signified by a high Kp, uu value (0.85). Altogether, our study highlights Ph-HTBA as a promising candidate for CaMKII alpha-associated pharmacological interventions and future clinical development.

KW - PROTEIN-KINASE-II

KW - GAMMA-HYDROXYBUTYRIC ACID

KW - GHB LIGANDS DESIGN

KW - ACCURATE DOCKING

KW - SODIUM OXYBATE

KW - BINDING

KW - MECHANISM

KW - RECEPTOR

KW - ANALOGS

KW - GLIDE

U2 - 10.1021/acs.jmedchem.2c00805

DO - 10.1021/acs.jmedchem.2c00805

M3 - Journal article

C2 - 36346645

VL - 65

SP - 15066

EP - 15084

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 22

ER -

ID: 328688588