Demonstrating Ligandability of the LC3A and LC3B Adapter Interface

Markus Hartmann; Jessica Huber; Jan S. Kramer; Jan Heering; Larissa Pietsch; Holger Stark; Dalibor Odadzic; Iris Bischoff; Robert Fürst; Martin Schröder; Masato Akutsu; Apirat Chaikuad; Volker Dötsch; Stefan Knapp; Ricardo M. Biondi; Vladimir V. Rogov; Ewgenij Proschak

doi:10.1021/acs.jmedchem.0c01564

Demonstrating Ligandability of the LC3A and LC3B Adapter Interface

Markus Hartmann, Jessica Huber, Jan S. Kramer, Jan Heering, Larissa Pietsch, Holger Stark, Dalibor Odadzic, Iris Bischoff, Robert Fürst, Martin Schröder, Masato Akutsu, Apirat Chaikuad, Volker Dötsch, Stefan Knapp, Ricardo M. Biondi, Vladimir V. Rogov, Ewgenij Proschak

Research output: Contribution to journal › Article › peer-review

Abstract

Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).

Original language	English
Pages (from-to)	3720-3746
Number of pages	27
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	7
DOIs	https://doi.org/10.1021/acs.jmedchem.0c01564
Publication status	Published - 2021 Apr 8
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.0c01564

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Hartmann, M., Huber, J., Kramer, J. S., Heering, J., Pietsch, L., Stark, H., Odadzic, D., Bischoff, I., Fürst, R., Schröder, M., Akutsu, M., Chaikuad, A., Dötsch, V., Knapp, S., Biondi, R. M., Rogov, V. V., & Proschak, E. (2021). Demonstrating Ligandability of the LC3A and LC3B Adapter Interface. Journal of Medicinal Chemistry, 64(7), 3720-3746. https://doi.org/10.1021/acs.jmedchem.0c01564

Demonstrating Ligandability of the LC3A and LC3B Adapter Interface. / Hartmann, Markus; Huber, Jessica; Kramer, Jan S.; Heering, Jan; Pietsch, Larissa; Stark, Holger; Odadzic, Dalibor; Bischoff, Iris; Fürst, Robert; Schröder, Martin; Akutsu, Masato; Chaikuad, Apirat; Dötsch, Volker; Knapp, Stefan; Biondi, Ricardo M.; Rogov, Vladimir V.; Proschak, Ewgenij.

In: Journal of Medicinal Chemistry, Vol. 64, No. 7, 08.04.2021, p. 3720-3746.

Research output: Contribution to journal › Article › peer-review

Hartmann, M, Huber, J, Kramer, JS, Heering, J, Pietsch, L, Stark, H, Odadzic, D, Bischoff, I, Fürst, R, Schröder, M, Akutsu, M, Chaikuad, A, Dötsch, V, Knapp, S, Biondi, RM, Rogov, VV & Proschak, E 2021, 'Demonstrating Ligandability of the LC3A and LC3B Adapter Interface', Journal of Medicinal Chemistry, vol. 64, no. 7, pp. 3720-3746. https://doi.org/10.1021/acs.jmedchem.0c01564

Hartmann, Markus ; Huber, Jessica ; Kramer, Jan S. ; Heering, Jan ; Pietsch, Larissa ; Stark, Holger ; Odadzic, Dalibor ; Bischoff, Iris ; Fürst, Robert ; Schröder, Martin ; Akutsu, Masato ; Chaikuad, Apirat ; Dötsch, Volker ; Knapp, Stefan ; Biondi, Ricardo M. ; Rogov, Vladimir V. ; Proschak, Ewgenij. / Demonstrating Ligandability of the LC3A and LC3B Adapter Interface. In: Journal of Medicinal Chemistry. 2021 ; Vol. 64, No. 7. pp. 3720-3746.

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title = "Demonstrating Ligandability of the LC3A and LC3B Adapter Interface",

abstract = "Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs). ",

author = "Markus Hartmann and Jessica Huber and Kramer, {Jan S.} and Jan Heering and Larissa Pietsch and Holger Stark and Dalibor Odadzic and Iris Bischoff and Robert F{\"u}rst and Martin Schr{\"o}der and Masato Akutsu and Apirat Chaikuad and Volker D{\"o}tsch and Stefan Knapp and Biondi, {Ricardo M.} and Rogov, {Vladimir V.} and Ewgenij Proschak",

note = "Funding Information: We thank Evelyn S{\"u}ss for technical assistance. E.P. was supported by the Deutsche Forschungsgemeinschaft (DFG, Heisenberg-Professur PR1405/7-1). A.C., S.K., and V.V.R. are grateful for support by the Structural Genomic Consortium (SGC). The SGC is a registered charity (No.: 1097737) that receives funds from AbbVie, Bayer AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN Grant 875510], Janssen, Merck KGaA (aka EMD in Canada and USA), Merck & Co (aka MSD outside Canada and USA), Pfizer, S{\~a}o Paulo Research Foundation-FAPESP, Takeda and Wellcome [106169/ZZ14/Z]. This research was supported by the DFG funded Collaborative Sonderforschungsbereich 1177 Autophagy (SFB1177) at Frankfurt University as well as the German Cancer Consortium (DKTK) and the Frankfurt Cancer Centre (FCI). We acknowledge the Paul Scherrer Institut, Villigen, Switzerland for provision of synchrotron radiation beamtime at beamline Beamline X06SA of the SLS. Publisher Copyright: {\textcopyright} 2021 American Chemical Society.",

year = "2021",

month = apr,

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doi = "10.1021/acs.jmedchem.0c01564",

language = "English",

volume = "64",

pages = "3720--3746",

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T1 - Demonstrating Ligandability of the LC3A and LC3B Adapter Interface

AU - Hartmann, Markus

AU - Huber, Jessica

AU - Kramer, Jan S.

AU - Heering, Jan

AU - Pietsch, Larissa

AU - Stark, Holger

AU - Odadzic, Dalibor

AU - Bischoff, Iris

AU - Fürst, Robert

AU - Schröder, Martin

AU - Akutsu, Masato

AU - Chaikuad, Apirat

AU - Dötsch, Volker

AU - Knapp, Stefan

AU - Biondi, Ricardo M.

AU - Rogov, Vladimir V.

AU - Proschak, Ewgenij

N1 - Funding Information: We thank Evelyn Süss for technical assistance. E.P. was supported by the Deutsche Forschungsgemeinschaft (DFG, Heisenberg-Professur PR1405/7-1). A.C., S.K., and V.V.R. are grateful for support by the Structural Genomic Consortium (SGC). The SGC is a registered charity (No.: 1097737) that receives funds from AbbVie, Bayer AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN Grant 875510], Janssen, Merck KGaA (aka EMD in Canada and USA), Merck & Co (aka MSD outside Canada and USA), Pfizer, São Paulo Research Foundation-FAPESP, Takeda and Wellcome [106169/ZZ14/Z]. This research was supported by the DFG funded Collaborative Sonderforschungsbereich 1177 Autophagy (SFB1177) at Frankfurt University as well as the German Cancer Consortium (DKTK) and the Frankfurt Cancer Centre (FCI). We acknowledge the Paul Scherrer Institut, Villigen, Switzerland for provision of synchrotron radiation beamtime at beamline Beamline X06SA of the SLS. Publisher Copyright: © 2021 American Chemical Society.

PY - 2021/4/8

Y1 - 2021/4/8

N2 - Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).

AB - Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).

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Demonstrating Ligandability of the LC3A and LC3B Adapter Interface

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