Pharmacological Characterization of SDX-7320/Evexomostat : a Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-Tumor and Anti-Metastatic Activity
Methionine aminopeptidase type 2 (MetAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. MetAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of MetAP2-specific substrates whose biological activity may be altered following MetAP2 inhibition, and additionally, that MetAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of MetAP2 using fumagillin analogs has established the anti-angiogenic and anti-tumor characteristics of these derivatives, however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting CNS toxicity. This report describes the physicochemical and pharmacological characterization of SDX-7320 (evexomostat), a polymer-drug conjugate of the novel MetAP2 inhibitor (MetAP2i) SDX-7539. In vitro binding, enzyme and cell-based assays demonstrated that SDX-7539 is a potent and selective MetAP2 inhibitor. In utilizing a high molecular weight, water-soluble polymer to conjugate the novel fumagillol-derived, cathepsin-released, MetAP2i SDX-7539, limitations observed with prior generation, small-molecule fumagillol derivatives were ameliorated including reduced CNS exposure of the MetAP2i, and prolonged half-life enabling convenient administration. Multiple xenograft and syngeneic cancer models were utilized to demonstrate the anti-tumor and anti-metastatic profile of SDX-7320. Unlike polymer-drug conjugates in general, reductions in small molecule-equivalent efficacious doses following polymer conjugation were observed. SDX-7320 has completed a Phase 1 clinical safety study in late-stage cancer patients and is currently being evaluated in multiple Phase 1b/2 clinical studies in patients with advanced solid tumors.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Molecular cancer therapeutics - (2024) vom: 26. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cornelius, Peter [VerfasserIn] |
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| Anmerkungen: |
Date Revised 26.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1158/1535-7163.MCT-23-0574 |
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| funding: |
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| PPN (Katalog-ID): |
NLM370196775 |
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| 245 | 1 | 0 | |a Pharmacological Characterization of SDX-7320/Evexomostat |b a Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-Tumor and Anti-Metastatic Activity |
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| 520 | |a Methionine aminopeptidase type 2 (MetAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. MetAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of MetAP2-specific substrates whose biological activity may be altered following MetAP2 inhibition, and additionally, that MetAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of MetAP2 using fumagillin analogs has established the anti-angiogenic and anti-tumor characteristics of these derivatives, however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting CNS toxicity. This report describes the physicochemical and pharmacological characterization of SDX-7320 (evexomostat), a polymer-drug conjugate of the novel MetAP2 inhibitor (MetAP2i) SDX-7539. In vitro binding, enzyme and cell-based assays demonstrated that SDX-7539 is a potent and selective MetAP2 inhibitor. In utilizing a high molecular weight, water-soluble polymer to conjugate the novel fumagillol-derived, cathepsin-released, MetAP2i SDX-7539, limitations observed with prior generation, small-molecule fumagillol derivatives were ameliorated including reduced CNS exposure of the MetAP2i, and prolonged half-life enabling convenient administration. Multiple xenograft and syngeneic cancer models were utilized to demonstrate the anti-tumor and anti-metastatic profile of SDX-7320. Unlike polymer-drug conjugates in general, reductions in small molecule-equivalent efficacious doses following polymer conjugation were observed. SDX-7320 has completed a Phase 1 clinical safety study in late-stage cancer patients and is currently being evaluated in multiple Phase 1b/2 clinical studies in patients with advanced solid tumors | ||
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| 700 | 1 | |a Petersen, John S |e verfasserin |4 aut | |
| 700 | 1 | |a Turnquist, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Dufour, Pierre J |e verfasserin |4 aut | |
| 700 | 1 | |a Dannenberg, Andrew J |e verfasserin |4 aut | |
| 700 | 1 | |a Shanahan, James M |e verfasserin |4 aut | |
| 700 | 1 | |a Carver, Bradley J |e verfasserin |4 aut | |
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