Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy

Kang Le; Michael J. Soth; Jason B. Cross; Gang Liu; William J. Ray; Jiacheng Ma; Sunil G. Goodwani; Paul J. Acton; Virginie Buggia-Prevot; Onno Akkermans; John Barker; Michael L. Conner; Yongying Jiang; Zhen Liu; Paul McEwan; Jennifer Warner-Schmidt; Alan Xu; Matthias Zebisch; Cobi Jacoba Johanna Heijnen; Brett Abrahams; Philip Jones

doi:10.1021/acs.jmedchem.3c00788

Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy

Kang Le, Michael J. Soth, Jason B. Cross, Gang Liu, William J. Ray, Jiacheng Ma, Sunil G. Goodwani, Paul J. Acton, Virginie Buggia-Prevot, Onno Akkermans, John Barker, Michael L. Conner, Yongying Jiang, Zhen Liu, Paul McEwan, Jennifer Warner-Schmidt, Alan Xu, Matthias Zebisch, Cobi Jacoba Johanna Heijnen, Brett AbrahamsPhilip Jones

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

2 Scopus citations

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathway─an active axon degeneration program that engages the dual leucine zipper kinase (DLK). DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiological conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases. We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN. Lead compound IACS-52825 (22) showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.

Original language	English (US)
Pages (from-to)	9954-9971
Number of pages	18
Journal	Journal of Medicinal Chemistry
Volume	66
Issue number	14
DOIs	https://doi.org/10.1021/acs.jmedchem.3c00788
State	Published - Jul 27 2023

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

MD Anderson CCSG core facilities

Research Animal Support Facility
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10.1021/acs.jmedchem.3c00788

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Le, K., Soth, M. J., Cross, J. B., Liu, G., Ray, W. J., Ma, J., Goodwani, S. G., Acton, P. J., Buggia-Prevot, V., Akkermans, O., Barker, J., Conner, M. L., Jiang, Y., Liu, Z., McEwan, P., Warner-Schmidt, J., Xu, A., Zebisch, M., Heijnen, C. J. J., ... Jones, P. (2023). Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy. Journal of Medicinal Chemistry, 66(14), 9954-9971. https://doi.org/10.1021/acs.jmedchem.3c00788

Le, K, Soth, MJ, Cross, JB, Liu, G, Ray, WJ, Ma, J , Goodwani, SG, Acton, PJ, Buggia-Prevot, V, Akkermans, O, Barker, J, Conner, ML, Jiang, Y, Liu, Z, McEwan, P, Warner-Schmidt, J, Xu, A, Zebisch, M, Heijnen, CJJ, Abrahams, B & Jones, P 2023, 'Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy', Journal of Medicinal Chemistry, vol. 66, no. 14, pp. 9954-9971. https://doi.org/10.1021/acs.jmedchem.3c00788

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title = "Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy",

abstract = "Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathway─an active axon degeneration program that engages the dual leucine zipper kinase (DLK). DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiological conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases. We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN. Lead compound IACS-52825 (22) showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.",

author = "Kang Le and Soth, {Michael J.} and Cross, {Jason B.} and Gang Liu and Ray, {William J.} and Jiacheng Ma and Goodwani, {Sunil G.} and Acton, {Paul J.} and Virginie Buggia-Prevot and Onno Akkermans and John Barker and Conner, {Michael L.} and Yongying Jiang and Zhen Liu and Paul McEwan and Jennifer Warner-Schmidt and Alan Xu and Matthias Zebisch and Heijnen, {Cobi Jacoba Johanna} and Brett Abrahams and Philip Jones",

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doi = "10.1021/acs.jmedchem.3c00788",

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AU - Le, Kang

AU - Soth, Michael J.

AU - Cross, Jason B.

AU - Liu, Gang

AU - Ray, William J.

AU - Ma, Jiacheng

AU - Goodwani, Sunil G.

AU - Acton, Paul J.

AU - Buggia-Prevot, Virginie

AU - Akkermans, Onno

AU - Barker, John

AU - Conner, Michael L.

AU - Jiang, Yongying

AU - Liu, Zhen

AU - McEwan, Paul

AU - Warner-Schmidt, Jennifer

AU - Xu, Alan

AU - Zebisch, Matthias

AU - Heijnen, Cobi Jacoba Johanna

AU - Abrahams, Brett

AU - Jones, Philip

PY - 2023/7/27

Y1 - 2023/7/27

N2 - Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathway─an active axon degeneration program that engages the dual leucine zipper kinase (DLK). DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiological conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases. We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN. Lead compound IACS-52825 (22) showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.

AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathway─an active axon degeneration program that engages the dual leucine zipper kinase (DLK). DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiological conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases. We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN. Lead compound IACS-52825 (22) showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.

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Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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