TNP-470: The Resurrection of the First Synthetic Angiogenesis Inhibitor

Mann-Steinberg, Hagit; Satchi‐Fainaro, Ronit

doi:10.1007/978-0-387-71518-6_35

Cited by 3 publications

(4 citation statements)

References 135 publications

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“…Fumagillin-bound METAP2 is stabilized and accumulates intracellularly, exerting additional pharmacodynamic effects including inhibition of MAPK activity ( 7, 8 ). Therefore, inhibition of METAP2 elicits multiple downstream effects leading to various physiological responses ( 9–11 ) including inhibition of tumor growth ( 12 ), metastasis ( 13 ), and angiogenesis, due to endothelial cell-cycle arrest in the late G 1 phase ( 14, 15 ). METAP2 has been reported to be overexpressed in many malignancies including breast, prostate, colorectal, esophageal, lung, lymphomas mesothelioma, and cholangiocarcinoma ( 16–20 ).…”

Section: Introductionmentioning

confidence: 99%

“…Despite promising clinical efficacy, TNP-470 suffered from dose-limiting neurological side effects, presumably due to penetration of the small molecule across the blood–brain barrier ( 24 ). Other challenges to its clinical development included poor aqueous solubility and a pharmacokinetic (PK) profile which necessitated frequent intravenous dosing due to its short half-life ( 9, 25 ).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Characterization of SDX-7320/Evexomostat: A Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-tumor and Anti-metastatic Activity

Cornelius,

Mayes,

Petersen

et al. 2024

Molecular Cancer Therapeutics

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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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacological Characterization of SDX-7320/Evexomostat: A Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-tumor and Anti-metastatic Activity

Cornelius,

Mayes,

Petersen

et al. 2024

Molecular Cancer Therapeutics

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show abstract

“…Fumagillin-bound MetAP2 is stabilized and accumulates intracellularly, exerting additional pharmacodynamic effects including inhibition of MAPK activity (7,8). Therefore, inhibition of MetAP2 elicits multiple downstream effects leading to various physiological responses (9)(10)(11) including inhibition of tumor growth (12), metastasis (13), and angiogenesis, due to endothelial cell cycle arrest in the late G1 phase (14,15). MetAP2 has been reported to be overexpressed in many malignancies including breast, prostate, colorectal, esophageal, lung, lymphomas mesothelioma, and cholangiocarcinoma (16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

“…Despite promising clinical efficacy, TNP-470 suffered from dose-limiting neurological side effects, presumably due to penetration of the small molecule across the blood-brain barrier (24). Other challenges to its clinical development included poor aqueous solubility and a pharmacokinetic (PK) profile which necessitated frequent intravenous (IV) dosing due to its short half-life (9,25).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Characterization of SDX-7320/Evexomostat: a Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-Tumor and Anti-Metastatic Activity

Cornelius,

Mayes,

Petersen

et al. 2024

Preprint

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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 vitrobinding, 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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