Discovery and Characterization of Brigimadlin, a Novel and Highly Potent MDM2-p53 Antagonist Suitable for Intermittent Dose Schedules

p53 is known as the guardian of the genome and is one of the most important tumor suppressors. It is inactivated in most tumors, either via tumor protein p53 (TP53) gene mutation or copy number amplification of key negative regulators, e.g., mouse double minute 2 (MDM2). Compounds that bind to the M...

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Published inMolecular cancer therapeutics Vol. 23; no. 12; pp. 1689 - OF14
Main Authors Gollner, Andreas, Rudolph, Dorothea, Weyer-Czernilofsky, Ulrike, Baumgartinger, Rosa, Jung, Peter, Weinstabl, Harald, Ramharter, Jürgen, Grempler, Rolf, Quant, Jens, Rinnenthal, Jörg, Pérez Pitarch, Alejandro, Golubovic, Bojana, Gerlach, Daniel, Bader, Gerd, Wetzel, Kristiane, Otto, Sebastian, Mandl, Christian, Boehmelt, Guido, McConnell, Darryl B, Kraut, Norbert, Sini, Patrizia
Format Journal Article
LanguageEnglish
Published United States American Association for Cancer Research 03.12.2024
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Abstract p53 is known as the guardian of the genome and is one of the most important tumor suppressors. It is inactivated in most tumors, either via tumor protein p53 (TP53) gene mutation or copy number amplification of key negative regulators, e.g., mouse double minute 2 (MDM2). Compounds that bind to the MDM2 protein and disrupt its interaction with p53 restore p53 tumor suppressor activity, thereby promoting cell cycle arrest and apoptosis. Previous clinical experience with MDM2-p53 protein-protein interaction antagonists (MDM2-p53 antagonists) has demonstrated that thrombocytopenia and neutropenia represent on-target dose-limiting toxicities that might restrict their therapeutic utility. Dosing less frequently, while maintaining efficacious exposure, represents an approach to mitigate toxicity and improve the therapeutic window of MDM2-p53 antagonists. However, to achieve this, a molecule possessing excellent potency and ideal pharmacokinetic properties is required. Here, we present the discovery and characterization of brigimadlin (BI 907828), a novel, investigational spiro-oxindole MDM2-p53 antagonist. Brigimadlin exhibited high bioavailability and exposure, as well as dose-linear pharmacokinetics in preclinical models. Brigimadlin treatment restored p53 activity and led to apoptosis induction in preclinical models of TP53 wild-type, MDM2-amplified cancer. Oral administration of brigimadlin in an intermittent dosing schedule induced potent tumor growth inhibition in several TP53 wild-type, MDM2-amplified xenograft models. Exploratory clinical pharmacokinetic studies (NCT03449381) showed high systemic exposure and a long plasma elimination half-life in patients with cancer who received oral brigimadlin. These findings support the continued clinical evaluation of brigimadlin in patients with MDM2-amplified cancers, such as dedifferentiated liposarcoma.
AbstractList p53 is known as the guardian of the genome and is one of the most important tumor suppressors. It is inactivated in most tumors, either via tumor protein p53 (TP53) gene mutation or copy number amplification of key negative regulators, e.g., mouse double minute 2 (MDM2). Compounds that bind to the MDM2 protein and disrupt its interaction with p53 restore p53 tumor suppressor activity, thereby promoting cell cycle arrest and apoptosis. Previous clinical experience with MDM2-p53 protein-protein interaction antagonists (MDM2-p53 antagonists) has demonstrated that thrombocytopenia and neutropenia represent on-target dose-limiting toxicities that might restrict their therapeutic utility. Dosing less frequently, while maintaining efficacious exposure, represents an approach to mitigate toxicity and improve the therapeutic window of MDM2-p53 antagonists. However, to achieve this, a molecule possessing excellent potency and ideal pharmacokinetic properties is required. Here, we present the discovery and characterization of brigimadlin (BI 907828), a novel, investigational spiro-oxindole MDM2-p53 antagonist. Brigimadlin exhibited high bioavailability and exposure, as well as dose-linear pharmacokinetics in preclinical models. Brigimadlin treatment restored p53 activity and led to apoptosis induction in preclinical models of TP53 wild-type, MDM2-amplified cancer. Oral administration of brigimadlin in an intermittent dosing schedule induced potent tumor growth inhibition in several TP53 wild-type, MDM2-amplified xenograft models. Exploratory clinical pharmacokinetic studies (NCT03449381) showed high systemic exposure and a long plasma elimination half-life in patients with cancer who received oral brigimadlin. These findings support the continued clinical evaluation of brigimadlin in patients with MDM2-amplified cancers, such as dedifferentiated liposarcoma.p53 is known as the guardian of the genome and is one of the most important tumor suppressors. It is inactivated in most tumors, either via tumor protein p53 (TP53) gene mutation or copy number amplification of key negative regulators, e.g., mouse double minute 2 (MDM2). Compounds that bind to the MDM2 protein and disrupt its interaction with p53 restore p53 tumor suppressor activity, thereby promoting cell cycle arrest and apoptosis. Previous clinical experience with MDM2-p53 protein-protein interaction antagonists (MDM2-p53 antagonists) has demonstrated that thrombocytopenia and neutropenia represent on-target dose-limiting toxicities that might restrict their therapeutic utility. Dosing less frequently, while maintaining efficacious exposure, represents an approach to mitigate toxicity and improve the therapeutic window of MDM2-p53 antagonists. However, to achieve this, a molecule possessing excellent potency and ideal pharmacokinetic properties is required. Here, we present the discovery and characterization of brigimadlin (BI 907828), a novel, investigational spiro-oxindole MDM2-p53 antagonist. Brigimadlin exhibited high bioavailability and exposure, as well as dose-linear pharmacokinetics in preclinical models. Brigimadlin treatment restored p53 activity and led to apoptosis induction in preclinical models of TP53 wild-type, MDM2-amplified cancer. Oral administration of brigimadlin in an intermittent dosing schedule induced potent tumor growth inhibition in several TP53 wild-type, MDM2-amplified xenograft models. Exploratory clinical pharmacokinetic studies (NCT03449381) showed high systemic exposure and a long plasma elimination half-life in patients with cancer who received oral brigimadlin. These findings support the continued clinical evaluation of brigimadlin in patients with MDM2-amplified cancers, such as dedifferentiated liposarcoma.
p53 is known as the guardian of the genome and is one of the most important tumor suppressors. It is inactivated in most tumors, either via tumor protein p53 (TP53) gene mutation or copy number amplification of key negative regulators, e.g., mouse double minute 2 (MDM2). Compounds that bind to the MDM2 protein and disrupt its interaction with p53 restore p53 tumor suppressor activity, thereby promoting cell cycle arrest and apoptosis. Previous clinical experience with MDM2-p53 protein-protein interaction antagonists (MDM2-p53 antagonists) has demonstrated that thrombocytopenia and neutropenia represent on-target dose-limiting toxicities that might restrict their therapeutic utility. Dosing less frequently, while maintaining efficacious exposure, represents an approach to mitigate toxicity and improve the therapeutic window of MDM2-p53 antagonists. However, to achieve this, a molecule possessing excellent potency and ideal pharmacokinetic properties is required. Here, we present the discovery and characterization of brigimadlin (BI 907828), a novel, investigational spiro-oxindole MDM2-p53 antagonist. Brigimadlin exhibited high bioavailability and exposure, as well as dose-linear pharmacokinetics in preclinical models. Brigimadlin treatment restored p53 activity and led to apoptosis induction in preclinical models of TP53 wild-type, MDM2-amplified cancer. Oral administration of brigimadlin in an intermittent dosing schedule induced potent tumor growth inhibition in several TP53 wild-type, MDM2-amplified xenograft models. Exploratory clinical pharmacokinetic studies (NCT03449381) showed high systemic exposure and a long plasma elimination half-life in patients with cancer who received oral brigimadlin. These findings support the continued clinical evaluation of brigimadlin in patients with MDM2-amplified cancers, such as dedifferentiated liposarcoma.
p53 is known as the guardian of the genome and is one of the most important tumor suppressors. It is inactivated in most tumors, either via tumor protein p53 ( TP53 ) gene mutation or copy number amplification of key negative regulators, e.g., mouse double minute 2 ( MDM2 ). Compounds that bind to the MDM2 protein and disrupt its interaction with p53 restore p53 tumor suppressor activity, thereby promoting cell cycle arrest and apoptosis. Previous clinical experience with MDM2–p53 protein–protein interaction antagonists (MDM2–p53 antagonists) has demonstrated that thrombocytopenia and neutropenia represent on-target dose-limiting toxicities that might restrict their therapeutic utility. Dosing less frequently, while maintaining efficacious exposure, represents an approach to mitigate toxicity and improve the therapeutic window of MDM2–p53 antagonists. However, to achieve this, a molecule possessing excellent potency and ideal pharmacokinetic properties is required. Here, we present the discovery and characterization of brigimadlin (BI 907828), a novel, investigational spiro-oxindole MDM2–p53 antagonist. Brigimadlin exhibited high bioavailability and exposure, as well as dose-linear pharmacokinetics in preclinical models. Brigimadlin treatment restored p53 activity and led to apoptosis induction in preclinical models of TP53 wild-type, MDM2 -amplified cancer. Oral administration of brigimadlin in an intermittent dosing schedule induced potent tumor growth inhibition in several TP53 wild-type, MDM2 -amplified xenograft models. Exploratory clinical pharmacokinetic studies (NCT03449381) showed high systemic exposure and a long plasma elimination half-life in patients with cancer who received oral brigimadlin. These findings support the continued clinical evaluation of brigimadlin in patients with MDM2 -amplified cancers, such as dedifferentiated liposarcoma.
Author Baumgartinger, Rosa
Otto, Sebastian
Rinnenthal, Jörg
Boehmelt, Guido
Rudolph, Dorothea
Jung, Peter
Sini, Patrizia
Gollner, Andreas
Grempler, Rolf
Bader, Gerd
Mandl, Christian
Gerlach, Daniel
Wetzel, Kristiane
Ramharter, Jürgen
Kraut, Norbert
Pérez Pitarch, Alejandro
McConnell, Darryl B
Weyer-Czernilofsky, Ulrike
Quant, Jens
Weinstabl, Harald
Golubovic, Bojana
AuthorAffiliation 2 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
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4 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
3 Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany
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Andreas Gollner and Dorothea Rudolph contributed equally to this article.
Mol Cancer Ther 2024;23:1689–702
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Snippet p53 is known as the guardian of the genome and is one of the most important tumor suppressors. It is inactivated in most tumors, either via tumor protein p53...
p53 is known as the guardian of the genome and is one of the most important tumor suppressors. It is inactivated in most tumors, either via tumor protein p53 (...
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StartPage 1689
SubjectTerms Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Drug Discovery
Drug Mechanisms
Female
First Disclosures
Humans
Indoles - administration & dosage
Indoles - pharmacokinetics
Indoles - pharmacology
Male
Mice
Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors
Rats
Small Molecule Agents
Spiro Compounds - administration & dosage
Spiro Compounds - pharmacokinetics
Spiro Compounds - pharmacology
Translational Research
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Xenograft Model Antitumor Assays
Title Discovery and Characterization of Brigimadlin, a Novel and Highly Potent MDM2-p53 Antagonist Suitable for Intermittent Dose Schedules
URI https://www.ncbi.nlm.nih.gov/pubmed/39259562
https://www.proquest.com/docview/3102881127
https://pubmed.ncbi.nlm.nih.gov/PMC11612618
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