First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure

Stefan Zwirner; Anan A. Abu Rmilah; Sabrina Klotz; Bent Pfaffenroth; Philip Kloevekorn; Athina A. Moschopoulou; Svenja Schuette; Mathias Haag; Roland Selig; Kewei Li; Wei Zhou; Erek Nelson; Antti Poso; Harvey Chen; Bruce Amiot; Yao Jia; Anna Minshew; Gregory Michalak; Wei Cui; Elke Rist; Thomas Longerich; Birgit Jung; Philipp Felgendreff; Omelyan Trompak; Prem K. Premsrirut; Katharina Gries; Thomas E. Muerdter; Georg Heinkele; Torsten Wuestefeld; David Shapiro; Markus Weissbach; Alfred Koenigsrainer; Bence Sipos; Eiso AB; Magdalena Ortiz Zacarias; Stephan Theisgen; Nicole Gruenheit; Saskia Biskup; Matthias Schwab; Wolfgang Albrecht; Stefan Laufer; Scott Nyberg; Lars Zender

doi:10.1016/j.cell.2024.02.023

First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure

Stefan Zwirner, Anan A. Abu Rmilah, Sabrina Klotz, Bent Pfaffenroth, Philip Kloevekorn, Athina A. Moschopoulou, Svenja Schuette, Mathias Haag, Roland Selig, Kewei Li, Wei Zhou, Erek Nelson, Antti Poso, Harvey Chen, Bruce Amiot, Yao Jia, Anna Minshew, Gregory Michalak, Wei Cui, Elke RistThomas Longerich, Birgit Jung, Philipp Felgendreff, Omelyan Trompak, Prem K. Premsrirut, Katharina Gries, Thomas E. Muerdter, Georg Heinkele, Torsten Wuestefeld, David Shapiro, Markus Weissbach, Alfred Koenigsrainer, Bence Sipos, Eiso AB, Magdalena Ortiz Zacarias, Stephan Theisgen, Nicole Gruenheit, Saskia Biskup, Matthias Schwab, Wolfgang Albrecht, Stefan Laufer, Scott Nyberg, Lars Zender

Transplant Surgery

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

Abstract

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

Original language	English (US)
Pages (from-to)	1666-1684.e26
Journal	Cell
Volume	187
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2024.02.023
State	Published - Mar 28 2024

Keywords

MKK4
drug discovery and development
first-in-human phase I trial
liver
liver failure
liver regeneration
partial hepatectomy

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2024.02.023

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Zwirner, S., Abu Rmilah, A. A., Klotz, S., Pfaffenroth, B., Kloevekorn, P., Moschopoulou, A. A., Schuette, S., Haag, M., Selig, R., Li, K., Zhou, W., Nelson, E., Poso, A., Chen, H., Amiot, B., Jia, Y., Minshew, A., Michalak, G., Cui, W., ... Zender, L. (2024). First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure. Cell, 187(7), 1666-1684.e26. https://doi.org/10.1016/j.cell.2024.02.023

Zwirner, S, Abu Rmilah, AA, Klotz, S, Pfaffenroth, B, Kloevekorn, P, Moschopoulou, AA, Schuette, S, Haag, M, Selig, R, Li, K, Zhou, W, Nelson, E, Poso, A, Chen, H, Amiot, B, Jia, Y, Minshew, A, Michalak, G, Cui, W, Rist, E, Longerich, T, Jung, B, Felgendreff, P, Trompak, O, Premsrirut, PK, Gries, K, Muerdter, TE, Heinkele, G, Wuestefeld, T, Shapiro, D, Weissbach, M, Koenigsrainer, A, Sipos, B, AB, E, Zacarias, MO, Theisgen, S, Gruenheit, N, Biskup, S, Schwab, M, Albrecht, W, Laufer, S, Nyberg, S & Zender, L 2024, 'First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure', Cell, vol. 187, no. 7, pp. 1666-1684.e26. https://doi.org/10.1016/j.cell.2024.02.023

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title = "First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure",

abstract = "Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.",

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author = "Stefan Zwirner and {Abu Rmilah}, {Anan A.} and Sabrina Klotz and Bent Pfaffenroth and Philip Kloevekorn and Moschopoulou, {Athina A.} and Svenja Schuette and Mathias Haag and Roland Selig and Kewei Li and Wei Zhou and Erek Nelson and Antti Poso and Harvey Chen and Bruce Amiot and Yao Jia and Anna Minshew and Gregory Michalak and Wei Cui and Elke Rist and Thomas Longerich and Birgit Jung and Philipp Felgendreff and Omelyan Trompak and Premsrirut, {Prem K.} and Katharina Gries and Muerdter, {Thomas E.} and Georg Heinkele and Torsten Wuestefeld and David Shapiro and Markus Weissbach and Alfred Koenigsrainer and Bence Sipos and Eiso AB and Zacarias, {Magdalena Ortiz} and Stephan Theisgen and Nicole Gruenheit and Saskia Biskup and Matthias Schwab and Wolfgang Albrecht and Stefan Laufer and Scott Nyberg and Lars Zender",

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T1 - First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure

AU - Zwirner, Stefan

AU - Abu Rmilah, Anan A.

AU - Klotz, Sabrina

AU - Pfaffenroth, Bent

AU - Kloevekorn, Philip

AU - Moschopoulou, Athina A.

AU - Schuette, Svenja

AU - Haag, Mathias

AU - Selig, Roland

AU - Li, Kewei

AU - Zhou, Wei

AU - Nelson, Erek

AU - Poso, Antti

AU - Chen, Harvey

AU - Amiot, Bruce

AU - Jia, Yao

AU - Minshew, Anna

AU - Michalak, Gregory

AU - Cui, Wei

AU - Rist, Elke

AU - Longerich, Thomas

AU - Jung, Birgit

AU - Felgendreff, Philipp

AU - Trompak, Omelyan

AU - Premsrirut, Prem K.

AU - Gries, Katharina

AU - Muerdter, Thomas E.

AU - Heinkele, Georg

AU - Wuestefeld, Torsten

AU - Shapiro, David

AU - Weissbach, Markus

AU - Koenigsrainer, Alfred

AU - Sipos, Bence

AU - AB, Eiso

AU - Zacarias, Magdalena Ortiz

AU - Theisgen, Stephan

AU - Gruenheit, Nicole

AU - Biskup, Saskia

AU - Schwab, Matthias

AU - Albrecht, Wolfgang

AU - Laufer, Stefan

AU - Nyberg, Scott

AU - Zender, Lars

PY - 2024/3/28

Y1 - 2024/3/28

N2 - Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

AB - Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

KW - MKK4

KW - drug discovery and development

KW - first-in-human phase I trial

KW - liver

KW - liver failure

KW - liver regeneration

KW - partial hepatectomy

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SN - 0092-8674

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JO - Cell

JF - Cell

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ER -

First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure

Abstract

Keywords

ASJC Scopus subject areas

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